Resveratrol-Containing Compositions and Methods of Use for Cardiac-Related Diseases

ABSTRACT

A resveratrol-containing composition capable of providing a therapeutic benefit to a subject such as modulation of a biological activity, improving cell transplantation therapy, or improving macular degeneration or dystrophy treatments. The compositions comprise trans-resveratrol, a metal chelator, and one or more additional antioxidants such as phenolic antioxidants or vitamin D.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application claims priority under 35 U.S.C. §120 to U.S. application Ser. No. 13/169,650, filed Jun. 27, 2011, which claims the benefit of U.S. Provisional Patent Application No. 61/359,024, filed on Jun. 28, 2010 and U.S. Provisional Patent Application No. 61/427,280, filed on Dec. 27, 2010, all of which are herein incorporated by reference in their entirety.

INCORPORATION OF TABLE

Table 3 in the present specification has been submitted as a separate electronic file, due to its large size, but should be understood as herein incorporated by reference in its entirety.

TABLES The patent application contains table(s) that have been included at the end of the specification.

BACKGROUND

Despite a high level of risk factors such as cholesterol, diabetes, hypertension and a high intake of saturated fat, French males display the lowest mortality rate from ischaemic heart disease and cardiovascular diseases in Western industrialized nations (36% lower than the USA and 39% lower than the UK). The so-called ‘French Paradox’ (a low mortality rate specifically from cardiovascular diseases) may be due mainly to the regular consumption of wine (Renaud, S. et al. (1998) Novartis Found. Symp. 216:208-222, 152-158).

Resveratrol (3,4′,5-trihydroxy-trans-stilbene) is a naturally occurring phenolic compound found, for example in grape skins, that has been demonstrated to have beneficial properties relating to health of humans. In particular, resveratrol is believed to be beneficial to the functioning of the heart and in extending the life of human cells. Resveratrol, when used in dietary supplements, is generally produced as an alcohol extract from plant sources.

Calorie restricted diets have been shown to enhance survival and longevity by up-regulating survival/longevity genes or down-regulating genes whose expression enhances cellular damage. Mice have been used extensively as a model for genetic expression comparisons with humans. Without limitation, the validity of murine models to human gene expression reflects the fact that 98% of human and murine gene are homologous, and that mice and humans have about the same number of genes (e.g., approximately 30,000).

Despite the established benefits of a calorie restricted diet, the severity of the required dietary regime has limited adoption of this approach to increasing longevity. It would therefore be desirable to provide an alternative route to obtaining the benefits of calorie restriction that would avoid the need for dietary regulation and that would be amenable to widespread adoption. The present embodiments are directed to this and other needs.

SUMMARY OF THE INVENTION

Embodiments of the present embodiments provide a composition that comprises trans-resveratrol, a metal chelating agent, and one or more additional antioxidants such as apigenin, caffeic acid, EGCG, ferulic acid, quercetin, or vitamin D, and methods of using the composition. The trans-resveratrol may be encapsulated to substantially preserve the biological activity of the composition from loss due to exposure of the trans-resveratrol to light or oxygen. Additional embodiments provide a method of protecting implanted stem cells by administering a composition that comprises trans-resveratrol, a metal chelating agent, and one or more additional antioxidants such as apigenin, caffeic acid, EGCG, ferulic acid, quercetin, or vitamin D in conjunction with or following stem cell implantation.

BRIEF DESCRIPTION OF THE FIGURES

FIG. 1 shows the change in body weight of mice administered resveratrol or a composition of the present embodiments (Longevinex®) relative to control animals and animals maintained on a calorie restricted diet.

FIG. 2 shows the serum insulin level of mice administered resveratrol or a composition of the present embodiments (Longevinex®) relative to control animals and animals maintained on a calorie restricted diet.

FIG. 3 shows the serum glucose level of mice administered resveratrol (P=0.97) or a composition of the present embodiments (Longevinex®) (P=0.07) relative to control animals and animals maintained on a calorie restricted diet (P=0.10).

FIG. 4 shows a schematic of a mechanism of action that is consistent with the observed biological activities of the compositions of the present embodiments.

FIG. 5 is a bar graph showing the effects of resveratrol and a composition of the present embodiments (Longevinex®) on aortic flow in isolated perfused rat hearts.

FIG. 6 is a bar graph showing the effects of resveratrol and a composition of the present embodiments (Longevinex®) on coronary flow in isolated perfused rat hearts.

FIG. 7 is a bar graph showing the effects of resveratrol and a composition of the present embodiments (Longevinex®) on left ventricular developed pressure (LVDP) in isolated perfused rat hearts.

FIG. 8 is a bar graph showing the effects of resveratrol and a composition of the present embodiments (Longevinex®) on the maximum first derivative of left ventricular developed pressure (LV[dP/dt]_(max)) in isolated perfused rat hearts.

FIG. 9 is a bar graph showing the effects of resveratrol and a composition of the present embodiments (Longevinex®) on myocardial infarct size in isolated perfused rat hearts.

FIG. 10 is a bar graph showing the effects of resveratrol and a composition of the present embodiments (Longevinex®) on cardiomycyte apoptosis in isolated perfused rat hearts.

FIG. 11 is a chart showing the hormetic action of resveratrol, in which resveratrol dose [x-axis] is plotted against the values of cardiac function, infarct size, and apoptosis.

FIG. 12 is a bar graph showing the effects of 100 mg/kg resveratrol and a composition of the present embodiments (Longevinex®) on myocardial infarct size in isolated rabbit hearts.

FIGS. 13A through 13F are bar graphs comparing the effects of resveratrol and a composition of the present embodiments (Longevinex®) on aortic flow in isolated perfused rat hearts (FIG. 13A), coronary flow in isolated perfused rat hearts (FIG. 13B), on left ventricular developed pressure (LVDP) in isolated perfused rat hearts (FIG. 13C), on the maximum first derivative of left ventricular developed pressure (LV[dP/dt]_(max)) in isolated perfused rat hearts (FIG. 13D), on myocardial infarct size in isolated perfused rat hearts (FIG. 13E), and on cardiomycyte apoptosis in isolated perfused rat hearts (FIG. 13F).

FIGS. 14A and 14B are a Box Whisker plot (FIG. 14A) and a profile plot (FIG. 14B) comparing the effects of resveratrol and a composition of the present embodiments (Longevinex®) on global miRNA expression.

FIGS. 15A through 15C are a scatter plot (FIG. 15A), heatmap (FIG. 15B) and principal component analysis (FIG. 15C) of all samples, comparing the effects of resveratrol and a composition of the present embodiments (Longevinex®) on miRNA expression pattern.

FIGS. 16A and 16B are bar graphs comparing the effects of resveratrol and a composition of the present embodiments (Longevinex®) on phosphorylation of ERK1/2 (FIG. 16A) and p38 MAPK (FIG. 16B).

FIGS. 17A through 17C are bar graphs (top) quantifying the results of Western blots (bottom) depicting the regulation of miR-20b and the effects of antagomiR-20b on VEGF, Western blot analysis (FIG. 17A), Western blot analysis of samples pre-treated with antagomiR-20b (FIG. 17B), and a Taqman Real-time PCR quantification (FIG. 17C).

FIGS. 18A and 18B are bar graphs (top) quantifying the results of Western blots (bottom) depicting the regulation of miR-20b and the effects of antagomiR-20b on HIF-1a expression, including Western blot analysis (FIG. 18A) and Western blot analysis of samples when pre-treated with antagomiR-20b (FIG. 18B).

FIG. 19 is a bar graph comparing the intracellular quantification of reactive oxygen species for resveratrol and a composition of the present embodiments (Longevinex®).

DETAILED DESCRIPTION

The present embodiments relate to a resveratrol-containing composition and especially a resveratrol-containing dietary composition (i.e., a composition amenable for oral ingestion by a recipient), and to methods of treatment and/or prophylaxis utilizing such compositions.

A. Compositions of the Present Embodiments

In a preferred embodiment, the composition comprises or consists essentially of one or more plant extracts comprising trans-resveratrol, a metal chelating agent, and one or more additional antioxidants such as apigenin, caffeic acid, EGCG, ferulic acid, quercetin, or vitamin D. These compositions exhibit numerous benefits as compared to pure resveratrol alone. Preferred compositions comprise resveratrol (preferably, a composition dosage of from about 1 mg/kg of body weight to about 2 g/kg of body weight (more preferably from about 1 mg/kg of body weight to about 5 mg/kg of body weight), a chelator, and an antioxidant, and may also comprise other compounds such as emulsifiers, glycosaminoglycans, etc.

In a preferred embodiment, the composition is intended for a human, and comprises or consists essentially of trans-resveratrol in an amount of about 1.0 to about 5.0 mg/kg of body weight, preferably about 1.5 to about 2.5 mg/kg or about 3 to about 4.5 mg/kg of patient, and one or more of the following:

-   -   (a) a chelator such as phytic acid in an amount of about 0.5 to         1.5, 0.75 to 1.25 mg/kg, or about 1 mg/kg of patient;     -   (b) an additional phenolic antioxidants such as quercetin or         ferulic acid in an amount of about 0.05 to 2, about 0.1 to 1.5,         or about 0.15 to 1 mg/kg of patient, or both quercetin and         ferulic acid in a total amount of about 0.15 to about 6, about         0.3 to 4.5, or about 0.45 to 3 mg/kg of patient; and     -   (c) an additional antioxidant such as Vitamin D in an amount of         about 2.5 to 2500 or about 25 to 1250 micrograms/kg of patient.

In a preferred embodiment, the composition comprises resveratrol and is sold commercially as Longevinex® (Resveratrol Partners, LLC, San Dimas, Calif.). Four different formulations of Longevinex® have been sold, each consisting essentially of a plant extract comprising trans-resveratrol, quercetin dihydrate, and rice bran extract comprising phytic acid. Each dose of Longevinex® is suitable for administration to an average (e.g., 70 kg) human once daily. Each dose (e.g., a capsule) of the first generation Longevinex® composition consists essentially of: 5 mg Vitamin E (as mixed tocopherols), 215 mg of a mixture of Vitis vinifera (French red wine grape) and Polygonum cuspidatum (giant knotweed) extracts together comprising 100 mg of trans-resveratrol, 25 mg quercetin dihydrate, 75 mg rice bran extract comprising phytic acid, 380 mg rice bran oil comprising ferulic acid, and 55 mg sunflower lecithin. Each dose (e.g., a capsule) of the second generation Longevinex® composition consists essentially of: 215 mg of a mixture of Vitis vinifera (French red wine grape) and Polygonum cuspidatum (giant knotweed) extracts together comprising 100 mg of trans-resveratrol, 25 mg quercetin dihydrate, 75 mg rice bran extract comprising phytic acid, and 50 mg ferulate. Each dose (e.g., two capsules) of the third generation Longevinex® consists essentially of a Polygonum cuspidatum extract comprising 100 mg of trans-resveratrol, 1000 IU of cholecaliferol (Vitamin D3), quercetin, and rice bran extract comprising phytic acid. Each dose (e.g., two capsules) of the fourth generation Longevinex®, sold as Longevinex Advantage™, consists essentially of a Polygonum cuspidatum extract comprising 100 mg of trans-resveratrol, 1000 IU of cholecaliferol (Vitamin D3), grape seed extract, quercetin, ferulic acid, cocoa extract, lutein, green tea extract, rice bran extract comprising phytic acid, and hyaluronan.

1. Resveratrol

Resveratrol has been ascribed multiple beneficial biological effects (see, e.g., U.S. Pat. No. 7,345,178, which listing of disclosed effects is herein incorporated by reference), including preventing or treating cardiovascular disease, preventing or treating cancer, preventing or treating macular degeneration, attenuating or preventing diseases associated with aging, and other conditions and illnesses, including the incidence or severity of neurodegenerative diseases such as Alzheimer's Disease and Parkinson's Disease, and anti-inflammatory activity.

Resveratrol, also known as 3,4′,5 trihydroxystilbene, naturally exists in cis- and trans-stereoisomeric forms. Studies have shown that resveratrol is biologically active, providing several health benefits including cancer prevention, anti-inflammatory properties, and cardiovascular effects. To maintain biological activity for an “extended period” of time, the small molecules of plant or synthetic source preferably remain biologically active for time periods after which the molecules would naturally become biologically inactive due to degradation or molecular isomerization as a result of exposure to light, heat or oxygen. These destructive processes would likely occur during extraction, encapsulation or storage. For example, resveratrol possesses a half-life of approximately one day; consequently, it typically loses significant biological activity within two days of exposure to ambient conditions and during processing of dietary supplements. Preferably, the resveratrol used in the present compositions is entirely or primarily (e.g., more than 75, 80, 85, 90, or 95%) in the trans stereoisomeric form, i.e., trans-resveratrol.

Resveratrol may be synthesized chemically, or, more preferably, may be extracted from plant sources. Resveratrol is found in at least 72 species of plants distributed among 31 genera and 12 families. All of the families found to contain resveratrol belong to the spermatophytes division: Vitaceae, Myrtaceae, Dipterocarpaceae, Cyperaceae, Gnetaceae, Leguminosae, Pinaceae, Moraceae, Fagaceae, Liliaceae. Resveratrol has most often been reported in non-edible plants: vine, eucalyptus, spruce, and the tropical deciduous tree Bauhinia racemosa, Pterolobium Hexapetallum. Resveratrol is particularly found in grape skins and Giant Knotweed, cocoa and chocolate. Peanut sprouts are also a rich source of resveratrol.

In a preferred embodiment, the resveratrol is naturally derived, i.e., derived from at least one natural source such as plants (or parts thereof, such as tubers or fruit (including pulp and skins) from the plant). One preferred source is the seeds and/or skins of grapes, such as Vitis vinifera, Vitis labrusca, and Vitis rotundifolia. Another preferred source is Polygonum (Giant Knotweed) and, in particular, Polygonum cuspidatum (a species of giant knotweed). The natural derivation process includes those processes generally known in the art, including an extraction process in which a solvent is used to extract the small molecules from a natural source. The solvent includes aqueous solvents, organic solvents, and mixtures thereof. The solvent may include, but is not limited to, alcohols such as ethanol. By way of specific examples, the extracted material may include aqueous or organic solvent extracts of plants (or parts thereof), fruit juices (e.g., grape juice), and fermented liquors (e.g. wine) produced from plants or fruit juice, or mixtures of any of the foregoing. The extracted material may further include inert plant material naturally removed during the extraction process. The extracted material may be processed (physically and/or chemically) to remove the solvent and increase the concentration of the small molecules. For example, the solvent may be removed from the extract (e.g., by drying), leaving a dried powder.

In a preferred embodiment, the compositions comprise or consist essentially of a plant extract comprising trans-resveratrol, for example, a plant (grape) extract from Vitis vinifera, Vitis labrusca, or Vitis rotundifolia, a plant extract from a Polygonum species, or a combination of grape and/or Polygonum extracts. In a preferred embodiment, the compositions comprise or consist essentially of a mixture of grape and Polygonum extracts, each comprising trans-resveratrol. As used herein, the term “extract” or “plant extract” has its ordinary meaning of a concentrated pharmaceutical preparation of a plant obtained by removing active constituents (such as trans-resveratrol) with a suitable solvent or menstruum, which is evaporated away or otherwise removed to yield a residual mass of plant extract. The extract may be adjusted to a prescribed standard. Thus, it is understood by those skilled in the art that an “extract” or “plant extract” is not simply a pure active ingredient or ingredients, but instead contains secondary material from the source plant, for example, depending on the source plant, organic and inorganic salts, organic bases and acids, saponins, polyphenols, tannins, sugars, polysaccharides, etc.

In a preferred embodiment, trans-resveratrol is present in the composition in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 percent by weight, or is present in any range between any two of these amounts, e.g., between about 10 and 30%, in an amount lesser than or greater than any two of these amounts, e.g. lesser than 15% or greater than 75%, or in an amount lesser than or equal to, or greater than or equal to any two of these amounts, e.g., lesser than or equal to 15%. In a different preferred embodiment, the trans-resveratrol is present in the composition in an amount of about 5-50%, 7.5-45%, 10-40%, 12.5-35%, 15-30%, or 20-25% by weight. In another preferred embodiment, trans-resveratrol is present in the composition in an amount of about 5-30% or 10-20% by weight. In a different preferred embodiment, trans-resveratrol is present in the composition in an amount of about 10-35%, 12.5-30%, or 15-25%, or in an amount of about 15-35% or 20-30% by weight.

In a preferred embodiment, trans-resveratrol is present in the composition in an amount calculated to provide a dosage in milligrams trans-resveratrol per kilogram of the patient to whom the dosage will be administered, for example, in an amount of about 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75 or 5 mg trans-resveratrol per kilogram of patient, which is equivalent to a dosage of about 17.5, 35, 52.5, 70, 87.5, 105, 122.5, 140, 157.5, 175, 192.5, 210, 227.5, 245, 262.5, 280, 297.5, 315, 332.5, or 350 mg trans-resveratrol for the typical 70 kg human patient. In another preferred embodiment, trans-resveratrol is present in the composition in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47, 48, 49, 50, 51, 52, 53, 54, 55, 56, 57, 58, 59, 60, 61, 62, 63, 64, 65, 66, 67, 68, 69, 70, 71, 72, 73, 74, 75, 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89, 90, 91, 92, 93, 94, 95, 96, 97, 98, 99 or 100 mg trans-resveratrol per kilogram of patient, or about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195 or 200 mg trans-resveratrol per kilogram of patient. The trans-resveratrol may also be present in any range between any two of these amounts, e.g., between about 0.25 and 4 mg/kg or between about 26 and 33 mg/kg, in an amount lesser than any of these amounts, e.g., lesser than about 2.5 mg/kg or 50 mg/kg, in an amount lesser than or equal to any of these amounts, e.g., lesser than or equal to about 50 mg/kg, in an amount greater than any of these amounts, e.g., greater than about 1.25 mg/kg or 25 mg/kg, or in an amount greater than or equal to any of these amounts, e.g., greater than or equal to about 2.5 mg/kg or 100 mg/kg. In a preferred embodiment, trans-resveratrol is present in the composition in an amount of about 1.5 to about 2.5 mg/kg for a human patient, or about 3 to about 4.5 mg/kg for a human patient.

2. Chelators

As used herein the term “chelator” refers to an organic compound that bonds with and removes free metal ions from solution. Examples of suitable chelators include ethylenediaminetetraacetic acid (EDTA), histidine, antibiotic drugs of the tetracycline family, pyridoxal 2-chlorobenzoyl hydrazone, desferrioxamine, dexrazoxane, deferasirox, pyoverdine, pseudan, citrate, NDGA (nordihydroguaiaretic acid: 1,4-bis[3,4-dihydroxyphenyl]2,3-dimethylbutane), ferulic acid and phytic acid. Preferably, the compositions of the present embodiments will provide a composition dosage of chelator of from about 1 g to about 15 g, more preferably from about 2 g to about 12 g.

Phytic acid is a particularly preferred chelator for the purposes of the present embodiments. As used herein, the term “phytic acid” refers to inositol hexaphosphate ((2,3,4,5,6-pentaphosphonooxycyclohexyl)dihydrogen phosphate; also known as “IP6”). Phytic acid is found in substantial amounts in whole grains, cereals, legumes, nuts, and seeds, and is the primary energy source for the germinating plant. Phytic acid and its lower phosphorylated forms (such as IP3) are also found in most mammalian cells, where they assist in regulating a variety of important cellular functions. Phytic acid is preferably provided in the form of a rice bran extract comprising phytic acid. Phytic acid is reported to function as an antioxidant by chelating divalent cations such as copper and iron, thereby preventing the generation of reactive oxygen species responsible for cell injury and carcinogenesis. The preferred composition dosage of phytic acid (for example, as derived from rice bran as an extract) is in the range of 200-12,000 mg, more preferably about 250-2500 mg per day.

Phytic acid also is believed to reduce the availability of metallic minerals that serve as growth factors in tumor cells, and as an inhibitor of calcium crystallization. It is also believed to serve as a neutrophil priming and motility agent. Additionally, phytic acid has been found to be neuroprotective, and thus to attenuate the severity of conditions associated with neurodegenerative diseases (especially Parkinson's Disease, camptocormia, and Alzheimer's Disease). The components of the present compositions are believed to enhance such neuroprotection.

The chelator may be of natural or synthetic source and may include, but not be limited to synthetic chelators such as desferrioxamine, EDTA, and d-penicillamine, or natural chelators such as lactoferrin, inositol hexaphosphate (IP6), quercetin, catechin, ferulic acid, curcumin, ellagic acid, hydroxytyrosol, anthocyanidin, etc.

In a preferred embodiment, a chelator is present in the composition in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 percent by weight, or in an amount of about 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75 or 5 mg chelator per kilogram of patient, or is present in any range between any two of these amounts, in an amount lesser than or greater than any two of these amounts, or in an amount lesser than or equal to, or greater than or equal to any two of these amounts. In a preferred embodiment, the chelator is present in the composition in an amount of about 10 to 35%, 15 to 30%, 20 to 30%, or 17.5 to 27.5%, or in amount of about 0.5 to 1.5 mg/kg of patient, 0.75 to 1.25 mg/kg of patient, or about 1 mg/kg of patient.

3. Additional Antioxidants

Additional antioxidants, for example phenolic antioxidants or Vitamin D may be added to the compositions. The additional phenolic antioxidants may be, for example, quercetin, ferulic acid, butein, fisetin, myricetin, kaempferol, cis-resveratrol or piceatannol. The antioxidants are believed to provide improved bioavailability of resveratrol by inhibiting resveratrol glucuronidation, and also act synergistically with resveratrol or independently of resveratrol to provide beneficial function.

The additional phenolic antioxidants may belong to a number of chemical classes of phenolic antioxidant compounds, such as the chalcones (e.g., butein), the flavonoids, the hydroxycinnamic acids, and the stilbenoids (e.g., cis-resveratrol, piceatannol). The flavonoids are a large class of phenolic compounds including the flavanols (2-phenyl-3,4-dihydro-2H-chromen-3-ols such as the catechins and epicatechins), the flavones (2-phenylchromen-4-ones such as apigenin), and the flavonols (3-hydroxy-2-phenylchromen-4-ones such as quercetin).

In one embodiment, the additional phenolic antioxidant comprises or consists of an antioxidant chalcone such as butein. In another embodiment, the additional phenolic antioxidant comprises or consists of a hydroxycinnamic acid selected from the group consisting of caffeic acid, cichoric acid, chlorogenic acid, caftaric acid, coumaric acid, coutaric acid, diferulic acids, fertaric acid, and ferulic acid, or combinations thereof. In a preferred embodiment, the additional phenolic antioxidant comprises or consists of a combination of caffeic acid and ferulic acid. In yet another embodiment, the additional phenolic antioxidant comprises or consists of a stilbenoid selected from the group consisting of cis-resveratrol and piceatannol.

In a further embodiment, the additional phenolic antioxidant comprises or consists of a flavanol selected from the group consisting of catechin (C), catechin 3-gallate (CG), epicatechin (EC), epicatechin 3-gallate (ECG), epigallocatechin (EGC), epigallocatechin 3-gallate (EGCG), gallocatechin (GC), and gallocatechin 3-gallate (GCG), or combinations thereof. In a preferred embodiment, the additional phenolic antioxidant comprises or consists of epigallocatechin 3-gallate (EGCG). In another embodiment, the additional phenolic antioxidant comprises or consists of a flavone selected from the group consisting of apigenin, baicalein, chrysin, diosmin, luteolin, scutellarein, tangeritin, and wogonin, or combinations thereof. In a preferred embodiment, the additional phenolic antioxidant comprises or consists of apigenin. In yet another embodiment, the additional phenolic antioxidant comprises or consists of a flavonol selected from the group consisting of quercetin, kaempferol, myricetin, fisetin, isorhamnetin, pachypodol, and rhamnazin, or combinations thereof. In a preferred embodiment, the additional phenolic antioxidant comprises or consists of quercetin.

The additional phenolic antioxidant may also comprise or consist of a combination of phenolic antioxidants, for example one or more flavonoids combined with one or hydroxycinnamic acids, etc. In one embodiment, the additional phenolic antioxidant comprises or consists of a combination of apigenin, caffeic acid, EGCG, ferulic acid, and quercetin.

In a preferred embodiment, one or more additional phenolic antioxidants are present in the composition in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 percent by weight, or in an amount of about 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75 or 5 mg additional phenolic antioxidant per kilogram of patient, or is present in any range between any two of these amounts, in an amount lesser than or greater than any two of these amounts, or in an amount lesser than or equal to, or greater than or equal to any two of these amounts. In a preferred embodiment, the one or more additional phenolic antioxidants are present in the composition in an amount of about 1 to 25%, 2.5 to 20%, 5 to 15%, or 7.5 to 12.5%, or in an amount of about 5-10%, or in an amount of about 0.05 to 2, about 0.1 to 1.5, or about 0.15 to 1 mg/kg of patient, or in an amount of about 0.15 to about 6, about 0.3 to 4.5, or about 0.45 to 3 mg/kg of patient.

A non-phenolic antioxidant such as vitamin D may also be present in the compositions. As used herein, the term “Vitamin D” refers to a fat-soluble prohormone. Two major forms of vitamin D are vitamin D₂ (ergocalciferol) and vitamin D₃ (cholecalciferol) (DeLuca, H. F. et al. (1998) Nutr. Rev. 56:S4-S10). Vitamin D exhibits many biological actions. While vitamin D is widely known for its ability to stave off bone disease (rickets in growing children, osteoporosis in senior adults), it is becoming a central player in the battle against cancer. Regarding the role of vitamin D in immunity and cancer, vitamin D improves the chemotactic (affinity for) neutrophils to mobilize and migrate. Patients with rickets due to vitamin D deficiency are observed to have sluggish neutrophils that cannot migrate properly. Vitamin D stimulates the maturation of monocytes to macrophages. This results in an enlarged army of immune fighting cells to mount against tumors. Vitamin D is widely available commercially, and such preparations are suitable for the purposes of the present embodiments.

Vitamin D is essential for optimal muscle, bone, brain, immune and cardiovascular health and is undergoing re-discovery by aging researchers worldwide. Vitamin D supplementation up to 2000 IU has been shown to significantly reduce mortality rates, thus adding vitamin D to the lineup of molecules now considered to be true longevity factors (Autier, P. et al. (2007) Arch Intern Med. 167(16):1730-1737). Its anti-calcifying properties (Zittermann, A. et al. (2007) Curr. Opin. Lipidology 18(1):41-46) qualify vitamin D as another powerful agent that inhibits progressive overmineralization in the human body with advancing age and parallels the action of other mineral chelators in the compositions of the present embodiments. While the 1200 IU dose is three times more than the Recommended Daily Allowance, it is well within the Safe Upper Limit established by the National Academy of Sciences (2000 IU) and corresponds with a supplemental dosage recently found to be beneficial in a human clinical trial (Lappe, J. M. et al. (2007) Amer. J. Clin. Nutr. 85(6):1586-1591). A 2,000 IU dosage is roughly equivalent the natural vitamin D3 produced by 15-30 minutes of total-body summer sun exposure at noontime at a southern latitude, for which no side effects have been reported. Preferably, the compositions of the present embodiments will provide a composition dosage of vitamin D of from about 100 IU to about 100,000 IU, more preferably from about 1,000 IU to about 50,000 IU.

Vitamin D3 works as an agent that mimics the response to a biological stressor, solar radiation. In particular, vitamin D3 upregulates protective genes involved in activation of the immune system, particularly neutrophil count and motility, and aids in overcoming the decline in endogenous vitamin D3 production with advancing age due to thickening of the skin, which reduces sun/skin production of vitamin D. Furthermore, vitamin D3 works synergistically to breakdown IP6 to IP3, thought to be a major active molecule. Resveratrol also works synergistically to sensitize cells to vitamin D3 (sensitizes the vitamin D receptor on the cell surface). Vitamin D serves to break down IP6 to IP3, which is its primary active form. Vitamin D is also believed to act as an immune system enhancing agent, boosting innate immunity in humans. In this capacity, vitamin D has been shown experimentally to have important cancer-preventive and cancer-curing properties. Resveratrol increases the sensitivity of the vitamin D receptor on the surface of cells, and thus is believed to act as an enhancing agent for vitamin D and as an anti-cancer agent. Resveratrol up-regulates the vitamin D receptor on the surface of healthy and cancer cells, and sensitizes cancer cells to vitamin D. Resveratrol is also believed to be a monoamine oxidase inhibitor (MAO Inhibitor).

In a preferred embodiment, Vitamin D is present in the composition in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 percent by weight, or in an amount of about 0.25, 0.5, 0.75, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75 or 5 micrograms (μg) Vitamin D per kilogram of patient, or in an amount of about 5, 10, 15, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90, 95, 100, 105, 110, 115, 120, 125, 130, 135, 140, 145, 150, 155, 160, 165, 170, 175, 180, 185, 190, 195, 200, 225, 250, 275, 300, 325, 350, 375, 400, 425, 450, 475, 500, 525, 550, 575, 600, 625, 650, 675, 700, 725, 750, 775, 800, 825, 850, 875, 900, 925, 950, 975, 1000, 1100, 1200, 1300, 1400, 1500, 1600, 1700, 1800, 1900, 2000, 2100, 2200, 2300, 2400, 2500, 2600, 2700, 2800, 2900 or 3000 micrograms (μg) Vitamin D per kilogram of patient. Vitamin D may also be present in an amount of about 50-150,000 IU, about 100-100,000 IU, or about 1000 to 50,000 IU, where 1 microgram (μg) Vitamin D is equivalent to 40 IU. Vitamin D may also be present in any range between any two of these amounts, in an amount lesser than or greater than any two of these amounts, or in an amount lesser than or equal to, or greater than or equal to any two of these amounts. In a preferred embodiment, Vitamin D is present in the composition in an amount of about 2.5 to 2500 micrograms/kg of patient, or about 25 to 1250 micrograms/kg of patient.

4. Glycosaminoglycans

The compositions may comprise collagen-building nutrients (such as vitamin C-ascorbate, lysine, proline, etc.), and/or a glycosaminoglycan such as a shortened (low molecular weight) chain of hyaluronic acid (HA) or its singular components (glucosamine, glucuronate) or chondroitin sulfate, which are linear disaccharides (sugar-like molecules) that serve as structural components of cartilage, but in this combination serve as synergistic co-healing agents in non-cellular (connective) tissue that surrounds living cells. The collagen-building nutrients encourage the generation of collagen and small molecules that operate on intra-cellular basis.

As used herein, the term “hyaluronic acid” (also known as hyaluronan) refers to linear polymer composed of repeating disaccharides of D-glucuronic acid and D-N-acetylglucosamine, linked together via alternating β-1,4 and β-1,3 glycosidic bonds ([-β(1,4)-GlcUA-β(1,3)-GlcNAc-]_(n)). Hyaluronic acid can be 25,000 disaccharide repeats (n) in length. Hyaluronic acid is a water-retaining molecule that is generated naturally in the human body but in decreasing amounts as the body ages. Hyaluronic acid is a multifunctional glycosaminoglycan that forms the basis of the pericellular matrix of cells. Hyaluronic acid is synthesized by 3 different but related enzymes. U.S. Patent Application Publication 2004/0234497 discloses the use of hyaluronic acid for cancer drug delivery. The entire disclosure of that publication is incorporated herein by reference. Hyaluronic acid has been traditionally extracted from rooster combs, from bovine or fish vitreous humor, from microbial production or from other sources. Most preferably, the hyaluronic acid of the present embodiments is obtained from rooster combs. Hyaluronic acid is widely available commercially, and such preparations are suitable for the purposes of the present embodiments. Preferably, the compositions of the present embodiments will provide a composition dosage of hyaluronic acid of from about 1 mg to about 400 mg, more preferably from about 50 mg to about 200 mg.

Hyaluronic acid is the water gelling molecule of the human body which serves as its scaffolding and hydrating agent. As aging progresses, less hyaluronic acid is produced, resulting in wrinkled skin, thinning hair, unlubricated joints. The chelators of the present composition also help to preserve hyaluronic acid in the body. The hyaluronic acid component and the mineral chelating components (e.g., resveratrol, quercetin, phytic acid IP6, ferulate) work as a total anti-aging strategy to maintain youthful function within cells and connective tissues. Hyaluronic acid is believed to have an affinity to cancer cells. It is believed to serve as a delivery and targeting (drug delivery agent) molecule in blood circulation and to address aging of the connective tissue. The collapse and loss of integrity of connective tissue between cells provides the signs of aging (e.g., skin wrinkling, hair thinning, joint stiffness, loss of stature, etc.). The addition of hyaluronic acid to the present compositions is believed to activate fibroblast cells in the human body to produce additional hyaluronic acid, thus serving to preserve connective tissue (collagen) in a youthful state.

In a preferred embodiment, one or more glycosaminoglycans are present in the composition in an amount of about 1, 2, 3, 4, 5, 6, 7, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 19, 20, 25, 30, 35, 40, 45, 50, 55, 60, 65, 70, 75, 80, 85, 90 or 95 percent by weight, or in an amount of about 0.01, 0.05, 0.1, 0.15, 0.2, 0.25, 0.3, 0.35, 0.4, 0.45, 0.5, 0.55, 0.6, 0.65, 0.7, 0.75, 0.8, 0.85, 0.9, 0.95, 1, 1.25, 1.5, 1.75, 2, 2.25, 2.5, 2.75, 3, 3.25, 3.5, 3.75, 4, 4.25, 4.5, 4.75, 5, 5.25, 5.5, 5.75, 6, 6.25, 6.5, 6.75, 7, 7.25, 7.5, 7.75, 8, 8.25, 8.5, 8.75, 9, 9.25, 9.5, 9.75 or 10 mg glycosaminoglycan per kilogram of patient, or is present in any range between any two of these amounts, in an amount lesser than or greater than any two of these amounts, or in an amount lesser than or equal to, or greater than or equal to any two of these amounts. In a preferred embodiment, the one or more glycosaminoglycans are present in the composition in an amount of about 0.25 to 4, 0.5 to 3.75, or 0.75 to 3.5 mg/kg of patient.

5. Other Components

The compositions of the present embodiments may contain additional components, including additional active components that act to enhance resveratrol biological activity and inactive compounds (e.g., flavorants, sweeteners, dyes, vitamins, amino acids (e.g., lysine, proline, etc.), minerals, nutrients, etc.). For example, tocopherols such as Vitamin E, sunflower lecithin, grape seed extract, cocoa extract, lutein, and green tea extract are preferred additional components in certain embodiments. Emulsifiers, fillers, binding agents, and the like may also be included in the compositions of the present embodiments.

The combination of the present embodiments is intended for human or animal oral intake as a dietary supplement. For example, such compositions may comprise a combination of resveratrol and hyaluronan in a dietary supplement that serves to heal a variety of illnesses including some cancers. Resveratrol is known to be an anti-cancer molecule and to have other healing and longevity enhancing properties. Hyaluronan (hyaluronic acid, HA) is taken as an oral supplement or can be given intravenously to target cancer cells. When combined with or attached to other molecules, hyaluronan will deliver other anti-cancer and healing agents such as resveratrol to tumor sites. The combination may or may not include a chelating agent, an antioxidant and/or an emulsifier. When encapsulated or otherwise applied together, with or without those additives, resveratrol and HA have powerful healing properties for animals and humans.

Most preferably, the compositions of the present embodiments stabilize resveratrol specific activity such that the resveratrol of the compositions has a specific activity that is greater than that of resveratrol maintained in the presence of oxygen gas, or maintained in the absence of a chelator, hyaluronic acid, or vitamin D. Preferably, the amounts of the non-resveratrol constituents of the compositions will stabilize the composition's resveratrol so that it exhibits at least 10% more activity, at least 20% more activity, at least 50% more activity, at least 2-times the activity, at least 5-times the activity, or at least 10-times the activity of resveratrol maintained in the presence of oxygen gas, or maintained in the absence of a chelator, hyaluronic acid, or vitamin D and so that it remains capable of exhibiting such specific activity over extended periods (for example, 1, 2, 4, 6, 10, 12, 18, 24, or 36 months or longer) at ambient conditions of temperature and humidity (i.e., without need for special precautions as to temperature or humidity).

In a preferred embodiment, the composition comprises or consists essentially of one or more plant extracts comprising trans-resveratrol and one or more of the following: a chelator such as phytic acid; one or more additional phenolic antioxidants such as quercetin or ferulic acid (ferulate); and Vitamin D. These compositions exhibit numerous benefits as compared to pure resveratrol alone. A particular benefit, explained in detail in Example 6 below, is that the present compositions do not exhibit the hormetic action characteristic of resveratrol (a dose-response relationship that is stimulatory at low doses, but detrimental at higher doses resulting in a J-shaped or an inverted U-shaped dose response curve). Instead, the present compositions have an L-shaped dose response curve, meaning that they are safe (non-toxic) even at high doses.

Preferred compositions comprise resveratrol (preferably, a composition dosage of from about 10 mg to about 2 g, more preferably from about 100 mg to about 500 mg), and at least one compound selected from the group consisting of an chelator, a glycosaminoglycan (e.g., hyaluronic acid), and vitamin D, and may also comprise other compounds such as antioxidants, emulsifiers, etc.

B. Methods of Treatment

The administration of the compositions of the present invention may be for a “prophylactic” or “therapeutic” purpose. The compositions of the present invention are said to be administered for a “therapeutic” purpose if the amount administered is physiologically significant to provide a therapy for an actual manifestation of the disease. When provided therapeutically, the composition is preferably provided at (or shortly after) the identification of a symptom of actual disease. The therapeutic administration of the compound serves to attenuate the severity of such disease or to reverse its progress. The compositions of the present invention are said to be administered for a “prophylactic” purpose if the amount administered is physiologically significant to provide a therapy for a potential disease or condition, e.g., to reduce the risk of heart attacks, to maintain health, to sustain a youthful appearance, to sustain function (e.g., to sustain a certain level of visual acuity, etc. When provided prophylactically, the composition is preferably provided in advance of any symptom thereof. The prophylactic administration of the composition serves to prevent or attenuate any subsequent advance of the disease.

Providing a therapy or “treating” refers to any indicia of success in the treatment or amelioration of an injury, pathology or condition, including any objective or subjective parameter such as abatement, remission, diminishing of symptoms or making the injury, pathology or condition more tolerable to the patient, slowing in the rate of degeneration or decline, making the final point of degeneration less debilitating, or improving a patient's physical or mental well-being. The treatment or amelioration of symptoms can be based on objective or subjective parameters, including the results of a physical examination, neuropsychiatric examination, and/or laboratory methods.

Preferred subjects for treatment include animals, most preferably mammalian species such as humans, and domestic animals such as dogs, cats and the like, subject to disease and other pathological conditions. A “patient” refers to a subject, preferably mammalian (including human). In a preferred embodiment, the subject or patient is a human, and in a more preferred embodiment, the subject or patient is a human having or at risk of developing one or more of cardiovascular disease, cancer, macular degeneration, aging, neurodegenerative diseases (e.g., Alzheimer's Disease, Parkinson's Disease, etc.) and inflammation.

A variety of administration routes for the compositions of the present invention are available. The particular mode selected will depend, of course, upon the particular therapeutic agent selected, whether the administration is for prevention, diagnosis, or treatment of disease, the severity of the medical disorder being treated and dosage required for therapeutic efficacy. The methods of the present embodiments may be practiced using any mode of administration that is medically acceptable, and produces effective levels of the active compounds without causing clinically unacceptable adverse effects. Such modes of administration include, but are not limited to, oral, buccal, sublingual, inhalation, mucosal, rectal, intranasal, topical, ocular, periocular, intraocular, transdermal, subcutaneous, intra-arterial, intravenous, intramuscular, parenteral, or infusion methodologies. In a preferred embodiment, administration is oral.

The dosage schedule and amounts effective for therapeutic and prophylactic uses, i.e., the “dosing regimen”, will depend upon a variety of factors, including the stage of the disease or condition, the severity of the disease or condition, the general state of the patient's health, the patient's physical status, age and the like. In calculating the dosage regimen for a patient, the mode of administration also is taken into consideration. The dosage regimen also takes into consideration pharmacokinetics parameters well known in the art, i.e., the rate of absorption, bioavailability, metabolism, clearance, and the like (see, e.g., Hidalgo-Aragones (1996) J. Steroid Biochem. Mol. Biol. 58:611-617; Groning (1996) Pharmazie 51:337-341; Fotherby (1996) Contraception 54:59-69; Johnson (1995) J. Pharm. Sci. 84:1144-1146; Rohatagi (1995) Pharmazie 50:610-613; Brophy (1983) Eur. J. Clin. Pharmacol. 24:103-108). The state of the art allows the clinician to determine the dosage regimen for each individual patient, therapeutic agent and disease or condition treated. Single or multiple administrations of the compositions of the present invention can be administered depending on the dosage and frequency as required and tolerated by the patient. The duration of prophylactic and therapeutic treatment will vary depending on the particular disease or condition being treated. Some diseases lend themselves to acute treatment whereas others require long-term therapy.

The compositions of the present embodiments may be administered to a subject alone, or to a subject who is or will receive another medicament or medical therapy. For example, in a preferred embodiment, the compositions of the present embodiments are co-administered to a subject with stem cell therapy or a treatment for macular degeneration or macular dystrophy. Co-administration may be simultaneous, serially, contemporaneously, or in any other suitable fashion.

In a preferred embodiment, said administration or co-administration provides a therapeutic or prophylactic benefit to the subject that is at least 1.5 fold, 2 fold, 2.5 fold, 3 fold, 3.5 fold, 4 fold, 4.5 fold, 5 fold, 5.5 fold, 6 fold, 6.5 fold, 7 fold, or more than 7 fold greater than the therapeutic or prophylactic benefit achieved by resveratrol alone, calorie restriction alone, or the other medicament or medical therapy (e.g., stem cell therapy or treatment of macular degeneration or macular dystrophy) alone. In another preferred embodiment, said co-administration provides a therapeutic or prophylactic benefit to the subject that is at least 125 percent, 150 percent, 175 percent, 200 percent, 250 percent, 300 percent, 350 percent, 400 percent, 450 percent, 500 percent, or more than 500 percent greater than the therapeutic or prophylactic benefit achieved by resveratrol alone, calorie restriction alone, or the stem cell therapy or treatment of macular degeneration or macular dystrophy alone.

The compositions of these embodiments enhance resveratrol's specific activity. The compositions of the present embodiments therefore find utility in the treatment or prophylaxis of diseases (or in the amelioration of the symptoms of diseases) such as cardiovascular disease, cancer, macular degeneration, aging, neurodegenerative diseases (e.g., Alzheimer's Disease, Parkinson's Disease, etc.) and inflammation in which the modulation of expression of “survival/longevity” genes and/or “damage inducing” genes is desired. Over time, as minerals such as calcium and iron accumulate in the human body, genes respond in deleterious ways. Liu, Y. et al. (2005) Ann. Clin. Lab. Sci. 35(3):230-239; Templeton, D. M. et al. (2003) Biochim. Biophys. Acta. 1619(2):113-124; Ikeda, H. et al. (1992) Hepatology 15(2):282-287. The present embodiments have particular utility in the treatment of macular degeneration, cancer and the conditions of aging.

Additional embodiments provide a method of ameliorating a symptom associated with an existing disease of an individual or for preventing the onset of the symptom in an individual prior to the occurrence of the disease in the individual, which comprises administering to the individual, a resveratrol-containing composition that modulates the concentration or activity, relative to resveratrol alone or calorie restriction, of the product of a survival/longevity gene or the product of a gene whose expression enhances cellular damage, wherein the resveratrol is provided in an amount effective to cause a modulation of the concentration or activity of the gene that ameliorates the symptom of the disease, and wherein the disease is selected from the group consisting of: cardiovascular disease, cancer, macular degeneration, a disease associated with aging, and inflammation. The embodiments further provide such methods wherein the disease is cancer, or a disease associated with aging (especially a neurodegenerative disease).

1. Stem-Cell-Related Methods

In one preferred embodiment, the compositions of the present embodiments are co-administered to a subject with cell implantation or transplant therapy such as stem cell implantation or injection. The cells may be stem cells or cells derived from stem cells, such as human embryonic stem cells, or adult stem cells such as bone marrow stem cells, cardiac stem cells, endothelial stem cells, hematopoietic stem cells, mammary stem cells, mesenchymal stem cells, neural crest stem cells, neural stem cells, olfactory adult stem cells, testicular stem cells, and very small embryonic-like “VSEL” stem cells, or combinations thereof, or cells derived from any of the foregoing. In a preferred embodiment, the transplanted cells are selected from the group consisting of cardiac stem cells, neural stem cells, and retinal pigment epithelial (RPE) cells.

The therapeutic benefits that may be shown in such cell transplant-related embodiments include one or more benefits selected from the group consisting of improved stem cell differentiation, improved cell adhesion, improved cell survival, improved cell proliferation, and combinations thereof.

Stem cells are recognized as the origin of all renewed cells in the human body. Stem cell implantation is believed to be of benefit in regeneration of damaged tissues, particularly for brain or heart tissue damaged by infarction or trauma, or tissue that does not normally exhibit rapid cell renewal and turnover. Chacko et al., Am. J. Physiol. Heart Circ. Physiol. 2009 396(5):H1263-73; Wakabayashi et al., J. Neurosci. Res. 2010 88(5):1017-25.

It is known that stem cell implantation has exhibited only limited or modest benefit in regeneration of damaged tissues, such as following a heart attack, and that animals treated with injected stem cells often progress to heart failure within weeks of stem cell implantation. Assmus et al., New England J. Med. 2006 355(12):1222-32; Shake et al., Ann. Thorac. Surg. 2002 73(6):1919-25. However, there does appear to be a reduction in short-term mortality exhibited by injection of stem cells in the oxygen-deprived (ischemic) cardiac tissue. Assmus et al., Circ. Res. 2007 100(8):1234-41.

It is also known that implanted stem cells must adhere to existing cell matrixes to facilitate tissue regeneration, and that free radicals impair stem cell tissue adherence. Song et al., Stem Cells 2010 28(3):555-63. Further, free radicals inhibit stem cell differentiation into desired cells (e.g., heart muscle, brain neuron, etc), and antioxidants have been demonstrated to enhance stem cell differentiation. Id.

Antioxidants have been demonstrated to reduce free radicals and improve stem cell adhesion and stem cell survival during and following implantation. Song et al., Stem Cells 2010 28(3):555-63; Rodriguez-Porcel et al., Mol. Imaging. Biol. 2010 12(3):325-34; Kashiwa et al., Tissue Eng. Part A. 2010 16(1):91-100. It is also known that resveratrol, a small molecule, enhances activity of endogenous antioxidants such as glutathione. superoxide dismutase (particularly manganese SOD), and catalase, and up-regulates the synthesis of stem cells themselves. Kao et al. Stem Cells Dev. 2010 19(2):247-58.

It has been demonstrated in animals that orally administered resveratrol helps to maintain a reduced cellular environment (less free radical activity) at a relatively low dose concentration (2.5 mg per kilogram of body weight, 175 mg per 160-lb human) which results in improved stem cell survival and enhanced cardiac function (ejection fraction, etc.). Gurusamy et al., J. Cell. and Mol. Medicine. 14(9):2235-39 (2010). In particular, Gurusamy et al. reported that pre-treatment of rats with low dose resveratrol for two weeks prior to injection of cardiac stem cells into the myocardium significantly improved cardiac functional parameters such as left ventricular ejection fraction and fractional shortening. Pre-treatment also enhanced stem cell survival and proliferation as demonstrated by differentiation of stem cells towards the regeneration of the myocardium.

In accordance with a preferred embodiment of the present invention, a matrix of small molecule antioxidants is combined with other small molecules and vitamin D3, and administered orally to preserve stem cells following implantation. Specifically, the matrix of small-molecule oral antioxidants includes, but is not limited to, resveratrol. This matrix is combined with other small molecules such as quercetin, IP6 phytate (inositol hexaphosphate), ferulic acid, EGCG (green tea), caffeic acid, apigenin, in combination with the vitamin/hormone vitamin D3. This combination exerts unexpected synergistic ability, over and above the expected additive properties of the individual constituents, to preserve stem cells following their implantation.

The dosage concentrations are lower than would be thought to be necessary from prior art experiments, thereby attesting to the synergism resulting from the combined constituents. For example, the dosage range of resveratrol in the combination is approximately 1.0 mg to approximately 5.0 mg/kilogram of body weight, and the total dosage concentration of all molecules is approximately 1.0 mg to approximately 5.0 mg/kilogram of body weight. The results of administering this mixture include greater genomic response, and improved tissue function (i.e., heart muscle activity—ejection fraction) equal to or greater than what has been exhibited in prior experiments. The mixture of constituents is preferably provided in a capsule but may be in pill, tablet, or liquid form.

2. Macular Degeneration

The prolongation of the human lifespan over the past few decades in the US has spawned the proliferation of macular degeneration, an age-related eye disease. While not resulting in total vision loss, the disease robs older adults of their central vision used for reading as well as color vision. Macular degeneration affects the visual center of the eye, called the macula. The macula is part of the retina where color-vision cells (cones) are located.

In a preferred embodiment, the compositions of the present embodiments are co-administered to a subject with one or more macular degeneration or macular dystrophy treatments selected from the group consisting of an anti-angiogenic medicament (e.g., anecortave acetate, bevacizumab, bevasiranib, pegaptanib sodium, ranibizumab, etc.), an anti-drusen medicament (e.g., ARC1905, copaxone, eculizumab, fenretinide, RN6G, etc.) implantation of a miniature telescope into the eye, laser photocoagulation, photodynamic therapy, or administration of another therapy such as alprostadil, AREDS2, cortical implants, macular translocation, micro-electrical stimulation, NT-501, photobiomodulation, radiation therapy, retinal implants or transplants, rheopheresis, cell transplantation (e.g., RPE cell transplantation, stem cell transplantation, etc.), submacular surgery, or a combination thereof.

The therapeutic benefits that may be shown in such macular-related embodiments include one or more benefits selected from the group consisting of preserved or improved eyesight (e.g., visual acuity), shrinkage or halting enlargement of visual defects, sparing cells in the central macula, permitting normal functioning of tissues surrounding or adjacent to the macula, decreases or prevention of increases in the amount of drusen or amyloid beta in the eyes, improving or increasing blood flow to the eye (and particularly the macula and retina), inhibition of blood vessel growth and leakage (e.g., angiogenesis), inhibition of scarring, improved retinal function, prevention or slowing of macular degeneration, prevention or slowing of cell death particularly retinal cells, reduction or elimination of eye lesions (e.g., geographic atrophy lesions), and combinations thereof.

Macular degeneration is a progressive, age-related disease that can be broken down into four stages. In the first stage, beginning in about the third decade of life, the inability of the “garbage cleaning” cells, called the retinal pigment epithelia (RPE), to engulf and remove cellular debris from the back of the eyes, results in the formation of small microscopic deposits called lipofuscin. Lipofuscin is formed by iron and copper-induced oxidation of cellular debris and its accumulation correlates with premature aging and shortened lifespan of organisms. The prevalence of macular degeneration is greater in Caucasians than persons with darkly-pigmented skin and Caucasians have more lipofuscin deposits in their retinas. Some of this cellular debris in the retina is comprised of used-up vitamin A that is shed from night-vision (rod) cells each morning in the human eye. The failure of the RPE cells to function results from accumulation of iron and calcium within the RPE. In the second stage, in about the fifth decade of life, there is progressive calcification of an underlying cellophane-thin retinal layer called Bruch's membrane, which resides between the RPE and the blood supply layer (choroid). While drusen that forms within the retina is partially composed of cholesterol, this lipid does not originate from the blood circulation or the liver where most cholesterol is produced. Calcifications within Bruch's membrane further impairs the exit of lipids (fats), protein, and cellular debris, from the photoreceptor layer, which results in the formation of yellow spots called drusen on the retina. Drusen can be observed during an eye examination using an ophthalmoscope. There is currently no method of removing drusen.

The death of the RPE cells is the third stage of this progressive disease. This is sometimes called RPE dropout. As the RPE cells are either impaired or have died, and Bruch's membrane is clogged with calcium, the photoreceptors then cannot be nourished and also begin to die off. There is currently no treatment for stages 1-3 of macular degeneration. Stage 1-3 is called the “dry” form of macular degeneration because it has not resulted in hemorrhage or edema or new blood vessel formation. About 85% of macular degeneration patients have the “dry” form of this disease. In the fourth stage, as breaks in Bruch's membrane occur, or Bruch's membrane becomes totally calcified, the photoreceptor layer is deprived of oxygen and new blood vessels form (called neovascularization) which can invade the photoreceptor layer in the macula and impair vision; or there may be leakage of blood serum or frank release of red blood cells, which results in edema or hemorrhage. This is the more advanced and sight-threatening form of macular degeneration, often called “wet” macular degeneration because of the presence of the leakage of blood serum or red blood cells into the photoreceptor layer. This stage of the disease, if caught early, can be treated with laser beams, which can seal up leaky blood vessels. However, this treatment is only effective in delaying the progression of the disease, not curing it.

The cell cleansing process facilitated by the lysosomes cannot keep up with the accumulation of metabolic waste over a lifetime. The parafoveal ring, where rod cell density is highest, and therefore more discs of used-up vitamin A are shed, is where macular degeneration begins, and where the highest concentration of lipofuscin is observed in the retina. Eventually, the RPE cells die off with advancing age, which increases the burden on the remaining RPE cells to maintain a healthy retina.

In the past, lipofuscin has been considered a harmless wear-and-tear byproduct of cellular metabolism. One aspect of the present embodiments relates to the recognition that lipofuscin, which forms from iron and copper-induced oxidation, and hardens within lysosomal bodies within retinal pigment epithelial cells, sensitizes the retina to damage by mild amounts of radiation and oxidation. The retina becomes increasingly sensitive to blue-light damage with advancing age. Drusen formation within the retina is associated with RPE cell inability to produce superoxide dismutase, an endogenous antioxidant enzyme. Mice deficient in superoxide dismutase develop features that are typical of age-related macular degeneration in humans. Superoxide dismutase protects retinal cells against unbound (free) iron. High iron diets and cellular environments have been shown to reduce superoxide dismutase activity.

Retinal photoreceptors and retinal pigment epithelial cells are believed to be especially vulnerable to damage by low-molecular weight complexes of iron. Since antioxidants in the blood circulation may not always be able to cross the blood-retinal barrier, the retina produces its own protective antioxidants that bind iron. Iron chelators inhibit the adverse effects of unbound (free) iron (not bound to proteins). Heme oxygenase also serves in a similar manner to iron chelators to prevent retinal damage induced by loose iron.

Numerous agents have been used experimentally to clear up lipofuscin and drusen. Statin drugs, commonly used to reduce blood serum levels of cholesterol, have also been tested to prevent lipofuscin deposits in animals. Statin drugs reduced lipofuscin formation but were toxic to the liver and brought about the early death of these animals. Piracetam, a derivative of the neurotransmitter GABA, now available as a dietary supplement, has been used successfully to reduce lipofuscin formation in brain tissues. Sorbinil is an enzyme inhibiting drug (aklose reductase inhibitor) that underwent unsuccessful human trials in the 1990s to prevent retinal problems associated with diabetes. Sorbinil has been shown to partially reduce lipofuscin deposits in the retinal pigment epithelium cells of rodents. Hydergine is a drug used to treat senile dementia. In a rodent study, hydergine was reported to have reduced brain lipofuscin levels, but also led to the early demise of the animals. The East Indian spice turmeric contains an antioxidant molecule called curcumin. Curcumin has been used in an experimental mouse study to reduce lipofuscin in the brain. Purslane is a flowering plant rich in magnesium, beta carotene and omega-3 oil. The provision of purslane to mice has been shown to reduce lipofuscin deposition in the brain of mice. In a lab dish study, sulforaphane, an antioxidant molecule found in Brussels sprouts and broccoli in 1992, has been used successfully to reduce lipofuscin deposits in RPE cells exposed to blue light.

Intraperitoneal administration of lipoic acid to aged rats leads to a reduction and elevation in lipofuscin and enzyme activity, respectively, in the cortex, cerebellum, striatum, hippocampus, and hypothalamus of the brain. These results suggest that lipoic acid, a natural metabolic antioxidant, should be useful as a therapeutic tool in preventing neuronal dysfunction in aged individuals. Lipoic acid, a natural antioxidant produced within living tissues, and also available as a dietary supplement, has been shown to protect RPE cells from oxidative damage in lab dish studies.

Lipofuscin formation dramatically increases in brain tissues following alcohol consumption. Supplementation with high-dose grape seed flavonols prevents increase lipofuscin formation. Lipofuscin is an end-product of lipid peroxidation which dramatically increases following ethanol consumption. Oolong and green tea drinks reverse the cognitive impairment and lipofuscin formation in mice. Epigallocatechin-3-gallate (EGCG), the major constituent of green tea, upregulates the activity of heme oxygenase in lab dish studies. Heme oxygenase is a protective enzyme against iron-induced oxidation, which occurs in the retina. It has been shown that the provision of supplemental estrogen decreases lipofuscin deposition in brain tissues. In a lab dish study, the provision of lutein and zeaxanthin to RPE cells reduced lipofuscin formation. In rodents given supplemental acetyl-L-carnitine, a decline in lipofuscin deposits has been measured in brain cells.

U.S. Pat. No. 5,747,536 describes the combined therapeutic use of L-carnitine, lower alkanoyl L-carnitines or the pharmacologically acceptable salts thereof, with resveratrol, resveratrol derivatives or resveratrol-containing natural products, for producing a medicament for the prophylaxis and treatment of cardiovascular disorders, peripheral vascular diseases and peripheral diabetic neuropathy. Melanin is an iron-binding antioxidant in the retina. As melanin levels decline in the retina with advancing age, there is a greater accumulation of lipofuscin.

In one embodiment, the present embodiments relates to a composition comprising a combination of: (a) a chelator such as inositol hexaphosphate (IP6), trans resveratrol, quercetin, or any polyphenol or bioflavonoid for metal(s) such as iron, copper, heavy metals; (b) a calcium chelator, such as inositol hexaphosphate (IP6); (c) a heme oxygenase activator, such as trans resveratrol, piceatannol, or any of resveratrol's natural analogs, or similar small molecules such as fisetin, myricetin, quercetin or other bioflavonoids; (d) an agent that lowers the affinity of oxygen for red blood cells, such as inositol hexaphosphate (IP6); and, optionally (e) other antioxidants such as vitamin E, lutein/zeaxanthin, alpha lipoic acid. The formulation functions to: (1) limit oxidation in retinal tissues (photoreceptors, retinal pigment epithelial cells (RPE), choroid, specifically mitochondria and lysosomes in RPE cells); (2) inhibit accumulation of lipofuscin deposits; (3) inhibit formation of drusen; and (4) limit calcifications to retinal tissues, especially Bruch's membrane.

3. Cancer

A major challenge in cancer therapy is to selectively target cytotoxic agents to tumor cells (Luo, Y. et al. (2000) Biomacromolecules 1(2):208-218). To decrease undesirable side effects of small molecule anticancer agents, many targeting approaches have been examined. One of the most promising methods involves the combination or covalent attachment of the cytotoxin with a macromolecular carrier, and in particular with hyaluronic acid (Luo, Y. et al. (1999) Bioconjug. Chem. 10(5):755-763; Luo, Y. et al. (1999) Bioconjug. Chem. 12(6):1085-1088; Luo, Y. et al. (2002) Pharm. Res. 19(4):396-402).

In one embodiment, the present embodiments relates to a resveratrol- and hyaluronic acid-containing composition for the treatment of cancer comprising: resveratrol, hyaluronan, and optionally vitamin D and/or IP6. It is believed that these components act synergistically with one another to mediate an effect in curing and/or in preventing cancer in humans and/or in improving immunity (e.g., immune system response) in patients threatened by tumors. This aspect of the present embodiments is based in part upon the recognition that natural molecules can boost cancer immunity, possibly in a manner similar to that observed in cancer-proof mice.

Upon provision with such composition, the sentinels of the innate immune system, dendritic cells, can be alerted and neutrophils, macrophages and natural killer cell activity can be significantly enhanced. The enhancement of vitamin D receptors via resveratrol is yet another major advantage of a combination approach to treat or prevent cancer. This approach appears to be more appropriate for senior adults, the highest risk group for cancer, who are often immune-compromised due to poor nutrition or lack of nutrient absorption. The fact that this therapy can now be immediately measured for effectiveness by non-invasive cancer cell counting technology means that expensive and equivocal tests on animals may not be required to prove efficacy.

Vitamin D exhibits many biological actions. While vitamin D is widely known for its ability to stave off bone disease (rickets in growing children, osteoporosis in senior adults), it is becoming a central player in the battle against cancer. Only recently is it also gaining attention as an antibiotic. Vitamin D-deficient mice exhibit a defective response from phagocyte cells in the face of infection or inflammation. Vitamin D deficiency is frequently associated with recurrent infections. Only about half of the macrophage cells accumulate at the site of inflammation in vitamin D-deficient animals compared to animals whose vitamin D levels are adequate.

To delve deeper into the role of vitamin D in immunity and cancer, vitamin D improves the chemotactic (affinity for) neutrophils to mobilize and migrate. Patients with rickets due to vitamin D deficiency are observed to have sluggish neutrophils that cannot migrate properly. Vitamin D stimulates the maturation of monocytes to macrophages. This results in an enlarged army of immune fighting cells to mount against tumors. Greater attention is now being given to vitamin D as an anti-cancer weapon because of studies which show supplemental vitamin D drastically reduces the risk for all types of cancer. A study that employed 1100 IU of vitamin D3 produced a 60-77% reduction in cancer risk among women in Nebraska in just a 4-year period.

Even though cancer risk is lowest in sunnier and Equatorial areas geographically, where vitamin D levels are higher in sun-exposed populations, the protective effect of vitamin D against cancer has been repeatedly dismissed or discounted. The consumption of vitamin D orally eliminates the concern of skin cancer emanating from overexposure to unfiltered sun rays. One of the latest analyses shows that the risk of colon cancer can be halved by taking 2000 IU of vitamin D per day and that the risk for breast cancer can be halved by taking 3500 IU of vitamin D per day. The median dietary intake of vitamin D is only about 230 IU per day, so the prospect of food fortification or supplementation to prevent or treat cancer now becomes real.

In order for tissues to utilize and benefit from vitamin D they must have proteins in their outer coat (cell membrane) that are designed to receive and bind to vitamin D. For example, about 80% of human breast tumors produce vitamin D cell receptors, though gene expression (production) of vitamin D receptor is at low levels. Vitamin D's ability to inhibit cancer may be heightened when it is aided by weak estrogen-like molecules in the diet. Resveratrol, an estrogen-like molecule commonly found in red wine, upregulates the vitamin D receptor in breast cancer cells without increasing cancer growth. Resveratrol, in effect, can sensitize breast cancer cells to the anti-cancer properties of vitamin D.

Laboratory experiments show that low-dose vitamin D3 does not reduce breast tumor cell growth but when combined with resveratrol, tumor cell numbers declines by 40%. At higher concentrations vitamin D3 reduces the number of breast cancer cells in a lab dish by about 25%, and this decline improves to 50% when combined with resveratrol. Whereas estrogen increases vitamin D receptor gene expression, it also stimulates breast tumor growth. Resveratrol does not have this drawback. Resveratrol potentiates or “weaponizes” the cancer-inhibiting effect of vitamin D. Furthermore, resveratrol by itself has been shown to calm the response of phagocytes to foreign invaders like germs and tumor cells. Resveratrol dampens production of reactive oxygen species (free radicals) and normalizes particle ingestion in macrophage cells. Therefore, resveratrol prevents the over-response of immune cells that can produce autoimmunity.

Resveratrol blocks cancer in so many ways that it is difficult to find a pathway for cancer that is not obstructed by resveratrol. Resveratrol induces the cell energy compartments in tumor cells, called mitochondria, to release an enzyme called cytochrome C oxidase that usually leads to a cascade of other enzymes that induce programmed cell death, called apoptosis. But a recent experiment also shows that resveratrol releases cytochrome C from ovarian tumor cells that leads to rapid cell death via a process called autophagy, a process where enzymes produced inside the tumor cell actually digest its innards (kind of a form of intracellular cannibalism). This is a form of cell suicide that resveratrol activates in tumor cells, but not healthy cells.

The contribution of innate immunity in surveillance of tumors is comparatively neglected in cancer biology. Phagocytosis, or “cell eating” is the cornerstone of the innate immune response. Focus has been directed to dendritic cells which are believed to be sentinels of the innate immune response. A limited number of immune-boosting agents have been investigated.

Skepticism surrounds interest in innate immune approaches to cancer treatment. For example, patients taking immune-suppressing don't necessarily develop cancer with more frequency. However, this may be misunderstood. An over-responsive immune system may lead to more tissue and organ damage that can be mortal to cancer patients. Most of the drugs used for breast cancer therapy induce immune suppression.

Nature's most potent iron chelator is inositol hexaphosphate (IP6), which is found in seeds and the bran fraction of whole grains. A low dosage of IP6 has been found to suppress the growth of rhabdomyosarcoma cells by 50%. Removal of IP6 allows these tumor cells to recover and grow once again. IP6-treated mice with injected tumors exhibit tumors that are 50 times smaller than non-treated mice. IP6 has also been shown to reduce the growth of injected fibrosarcoma cells in mice and prolong their survival. In examining the immune enhancing properties of IP6 it has been shown that it boosts production of free radicals (superoxide) and the cell digesting action of neutrophils in the presence of bacteria. IP6 increases the release of interleukin-8. The action of natural killer cells, which are involved in tumor cell destruction, is enhanced by IP6.

In one embodiment, the hyaluronic acid of such composition is conjugated to a chemotherapeutic agent. The embodiments particularly pertain to such compositions in which the chemotherapeutic agent is taxol. The embodiments particularly pertain to such compositions that additionally and preferably comprise a chelator, and/or vitamin D. Most malignant solid tumors contain elevated levels of Hyaluronic Acid (Rooney, P. et al. (1995) Int. J. Cancer 60(5):632-636) and these high levels of HA production provide a matrix that facilitates invasion (Hua, Q. et al. (1993) J. Cell. Sci. 106(Pt 1):365-375; Luo, Y. et al. (2000) Biomacromolecules 1(2):208-218). Thus chemotherapeutic agents that are conjugated to Hyaluronic Acid target tumor cells, and can provide an effective anti-tumor dosage at lower overall concentration.

In brief, a preferred method of conjugation entails forming an NHS(N-hydroxy-succimimide derivative of the chemotherapeutic agent. Such a derivative can be made by adding a molar excess of dry pyridine to a stirred solution of Taxol and succinic anhydride in CH₂Cl₂ at room temperature. The reaction mixture is then stirred for several days at room temperature and then concentrated in vacuo. The residue is dissolved in 5 ml of CH₂Cl₂ and the produced Taxol-2′-hemisuccinate can be purified on silica gel (washed with hexane; eluted with ethyl acetate) to give the desired product (Luo, Y. et al. (1999) Bioconjug. Chem. 10(5):755-763).

The N-hydroxy-succimimide derivative of the chemotherapeutic agent is then conjugated to adipic dihydrazido-functionalized hyaluronic acid. Adipic dihydrazido-functionalized hyaluronic acid is preferably prepared as described by Pouyani, T. et al. (1994) (Bioconjugate Chem. 5:339-347); Pouyani, T. et al. (1994) (J. Am. Chem. Soc. 116:7515-7522); Vercruysse, K. P. et al. (1997) (Bioconjugate Chem. 8:686-694). Thus, hyaluronic acid is preferably dissolved in water and an excess of adipic dihydrazide (ADH). The pH of the reaction mixture is adjusted to 4.75 by addition acid. Next, 1 equivalent of 1-Ethyl-3-[3-(dimethylamino)-propyl]carbodiimide (EDCI) is added in solid form. The pH of the reaction mixture is maintained at 4.75 by addition of acid. The reaction is quenched by addition of 0.1 N NaOH to adjust the pH of reaction mixture to 7.0. The reaction mixture is then transferred to pretreated dialysis tubing (Mw cutoff 3,500) and dialyzed exhaustively against 100 mM NaCl, then 25% EtOH/H2O and finally water. The solution is then filtered through 0.2 m cellulose acetate membrane, flash frozen, and lyophilized (Luo, Y. et al. (1999) Bioconjug. Chem. 10(5):755-763).

4. Aging

Calcification and rusting of cells impairs the cleansing of cellular debris (lipofuscin) from cells by enzymes produced by lysosomes, and results in impairment of cellular energy (ATP) produced by the mitochondria within cells. The compositions of the present embodiments inhibit and/or reverse cellular aging and/or connective tissue aging, and in particular, inhibit and/or reverse cellular aging and/or connective tissue aging caused by an accumulation of major minerals (e.g., iron, calcium, etc.). As a consequence, recipients of the compositions of the present embodiments exhibit enhanced longevity and enhanced cellular and connective tissue health and structure.

The human body ages at the cellular level by the slow accumulation of cellular debris called lipofuscin, which is facilitated by the progressive accumulation of iron and calcium within lysosomes and mitochondria. A cell cleansing and renewal process called autophagy prevents the accumulation of lipofuscin during the years of youthful growth, but this lysosomal mechanism declines once full growth is achieved due to accumulation of intracellular iron and calcium. Progressive inability to remove cellular debris results declining cell function and then premature death of the cell. A young cell efficiently removes debris from within. An old cell cannot efficiently remove debris and accumulates lipofuscin. The mitochondria, which provides cellular energy for lysosomal bodies to perform their cell cleansing activity, also becomes progressively calcified and ironized once childhood growth ceases. Only about 5% of mitochondria are functioning by age 80. Iron and calcium chelators are proposed to remedy mitochondrial aging which impacts cellular functions such as lysosomal enzymatic activity

The human body ages within connective tissue by failure of cells called fibroblasts to regenerate collagen and hyaluronic acid, the latter being a space-filling, water-holding molecule. Collagen formation is facilitated by vitamins and amino acids in the diet (vitamin C, lysine, proline). Fibroblasts can be stimulated to produce hyaluronic acid by estrogen, made naturally in the body, and by estrogen-like molecules found in plants, called phytoestrogens, provided in the diet of by hyaluronic acid itself. Young females, by virtue of the ability to produce estrogen, exhibit thicker hair, smoother skin and more flexible joints, due to the abundance of hyaluronic acid. All of these being attributes of youthfulness.

The inability to regenerate hyaluronic acid results in tissues losing their physical integrity by virtue of loss of the space-filling properties of hyaluronic acid. Without adequate hyaluronic acid, a dehydrated state results and tissues shrink and shrivel up. For example, skin that is lacking hyaluronic acid will appear wrinkled and dry. Joint spaces will lack the cushioning and space-filling needed to prevent bone from rubbing on bone. The eyes will begin to shrink in size. Hair will thin due to the lack of hydration. These are the most prominent visible or cosmetic signs of aging.

In one embodiment, the present embodiments address both cellular and extracellular (connective tissue) aging, thus (a) preserving youthful function of living cells by removal of excess minerals, largely calcium and iron, from cells, this facilitating autophagy (cleanup of cellular debris, such as lipofuscin, via lysosomal enzymes) and (b) invigorating and preserving production of hyaluronan by stimulation of fibroblasts by HA, phytoestrogens (resveratrol, quercetin, genistein, are a few), to inhibition of degradation of HA by provision of metal chelators, such as phytic acid, ferulate, quercetin, resveratrol, etc.

In one embodiment, the dietary supplement addresses both cellular and extra-cellular aging by its ability to stimulate renewal of living cells from within via enzymatic degradation of cellular debris by intracellular lysosomal bodies. This is facilitated by the inclusion of metal (iron, copper, heavy metal) and calcium chelating molecules within the formula. Lysosomes lose their ability to enzymatically digest cellular debris with the progressive accumulation of iron, copper and other metals, and the crystallization of calcium. In another embodiment, the dietary supplement stimulates fibroblasts to produce hyaluronic acid at youthful levels again. This is accomplished by provision of orally-consumed molecules that stimulate fibroblasts to produce hyaluronic acid. In another embodiment, the dietary supplement includes metal chelating molecules that help maintain youthful lysosomal function are identified as antioxidants, like vitamin E or vitamin C, lipoic acid, metal chelators like IP6 phytate, quercetin, bioflavonoids or polyphenols, resveratrol. Resveratrol works by its ability to stimulate production of heme oxygenase, an enzyme that helps to control iron. The dietary supplement may also include molecules that inhibit crystallization of calcium are magnesium and IP6 phytate, and orally consumed molecules that stimulate fibroblasts to produce hyaluronic acid are hyaluronic acid, glucosamine, chondroitin, or estrogen-like molecules such as genistein, lignans, hydroxytyrosol, or other molecules configured like estrogen. Orally consumed HA stimulates greater HA and chondroitin synthesis. Similarly, glucosamine stimulate fibroblasts to produce HA. Alternatively, or additionally, glucosamine stimulates synovial production of hyaluronic acid, which is primarily responsible for the lubricating and shock-absorbing properties of synovial fluid” (McCarty, M. F. (1998) Medical Hypotheses 50:507-510, 1998). In yet another embodiment, the dietary supplement may include orally consumed molecules that stimulate production of collagen are vitamin C, proline and lysine.

In such embodiment, the present embodiments relate to a resveratrol and hyaluronic acid-containing dietary supplement that restores youthful function and appearance to human cells and tissue. The embodiments particularly pertain to such compositions that additionally comprise a chelator, and/or vitamin D. Most preferably, the composition will comprise the chelator phytic acid (inositol hexaphosphate; IP6). The compositions of the present embodiments synergistically enhance the specific activity of the resveratrol and/or hyaluronic acid, and thus the compositions of the present embodiments provide an enhancement of activity above and beyond that obtained with the components administered individually. In such embodiment, the embodiments relates to a method for restoring youthful function and appearance to human cells and tissues comprising the following steps: (a) stimulating renewal of living cells from within via enzymatic degradation of cellular debris by intracellular lysosomal bodies (preferably by providing a metal chelating molecule that helps maintain youthful lysosomal function, such molecules comprising antioxidants, such as vitamin E or vitamin C, lipoic acid, metal chelators like IP6 phytate, quercetin, bioflavonoids or polyphenols, and/or resveratrol); and (b) stimulating fibroblasts to produce hyaluronic acid (comprises providing orally consumed molecules that stimulate fibroblasts to produce hyaluronic acid, such orally consumed molecules comprising, for example, hyaluronic acid, glucosamine, chondroitin, and/or estrogen-like molecules such as genistein, lignans, hydroxytyrosol, or other molecules configured like estrogen). Preferably, such stimulation is achieved by the dietary administration of a composition comprising the stated compounds, more preferably in combination with an orally consumable molecule that stimulates production of collagen, such molecules comprising, for example, vitamin C, proline and/or lysine.

The individual components of the composition are believed to act synergistically to enhance the effect of, for example, resveratrol. Without intending to be limited thereby, it is proposed that the body's control or chelation of iron and calcium regulates the rate of aging after full growth has been achieved. During childhood growth all the iron and calcium are directed towards production of new bone and new red blood cells (hemoglobin). The cessation of childhood growth results in excess iron, copper and calcium, which then progressively (a) calcifies and (b) rusts tissues. The lysosomes begin to accumulate iron and calcium, which results in their dysfunction. The mitochondria begin to malfunction as they also progressively rust and calcify. The compositions of the present embodiments are believed to be capable of limiting or slowing the progressive rusting and calcification of cells and cellular organelles to thereby facilitate a slowing or reversal of the aging process. The chelation is what controls the genes. Genes are then favorably upregulated or downregulated. Resveratrol and a copper chelator are believed to act: (1) as controllers of calcium concentration via upregulation of osteocalcin, the hormone that helps retain calcium in bones and (2) as controllers of iron concentration via heme oxygenase, an antioxidant enzyme.

MAO inhibitors and iron chelators have been proposed as treatments for Parkinson's disease (Youdim, M. B. et al. (2004) J. Neural. Transm. 111(10-11):1455-1471; Yáñez, M. et al. (2006) Eur. J. Pharmacol. 542(1-3):54-60; Bureau, G. et al. (2008) J. Neurosci. Res. 86(2):403-410; Singh, A. et al. (2003) Pharmacol. 68(2):81-88; Gao, X. et al. (2007) Am. J. Clin. Nutr. 86(5):1486-1494; Johnson, S. (2001) Med. Hypotheses 56(2):171-173). The compositions of the present embodiments which contain the MAO inhibitor and copper chelator, resveratrol, the iron chelator and MAO inhibitor, quercetin, and the broad metal chelator, phytic acid are particularly preferred for the treatment of neurodegenerative diseases (especially Parkinson's Disease, camptocormia, and Alzheimer's Disease) or in the amelioration of the symptoms of such diseases.

C. Modulation of Gene Product Concentration or Activity

In an example embodiment, the compositions are capable of modulating gene expression to an extent greater than that observed with resveratrol alone or with calorie restriction. In a preferred embodiment, the specific activity of the resveratrol in a resveratrol-containing composition has been stabilized or enhanced. As used herein, the term “specific activity” refers to the ratio of the extent of gene modulation (relative to control) per amount (mass) of administered resveratrol. In another preferred embodiment, the compositions up-regulate a survival/longevity gene or down-regulate a gene whose expression enhances cellular damage upon administration to a recipient.

The embodiments pertains to compositions that, upon administration to a recipient, increase the concentration or activity of a survival/longevity gene product and/or decrease the concentration or activity of a gene product that induces or causes cellular damage. As used herein, such increase (or decrease) in concentration or activity may be accomplished by any mechanism. For example, such increase (or decrease) may reflect a modulation of gene expression resulting in either increased (or decreased) expression of the gene encoding the survival/longevity gene product, or a gene that regulates (e.g., induces or represses) or whose product regulates such expression or activity. Alternatively, or conjunctively, such increase (or decrease) in concentration or activity may reflect a modulation of the recipient's ability to degrade or stabilize any such gene products. Alternatively, or conjunctively, such increase (or decrease) in concentration or activity may reflect a modulation of the recipient's ability to enhance, accelerate, repress or decelerate the activity of any such gene products.

The modulation of concentration or activity discussed above may be a modulation of intracellular, intercellular and/or tissue concentration or activity of such survival/longevity gene products or such gene products that induce or cause cellular damage. Such modulation may be identified by assays of DNA expression, assays of gene product activity, assays of the level of gene product, assays of the rate of gene product turnover, etc. conducted in one or more types of cells, tissues, etc.

An increase in the concentration of a survival/longevity gene product may result from, for example, increased transcription of the gene that encodes the survival/longevity gene product, increased transcription of a gene that induces the expression of the gene that encodes the survival/longevity gene product, decreased transcription of a gene that represses the expression of the gene that encodes the survival/longevity gene product, decreased degradation or enhanced stabilization of expressed molecules of the survival/longevity gene product (leading to the enhanced accumulation of the survival/longevity gene product). Similarly, a decrease in the concentration of a survival/longevity gene product may result from, for example, decreased transcription of the gene that encodes the survival/longevity gene product, decreased transcription of a gene that induces the expression of the gene that encodes the survival/longevity gene product, increased transcription of a gene that represses the expression of the gene that encodes the survival/longevity gene product, increased degradation or decreased stabilization of expressed molecules of the survival/longevity gene product (leading to the enhanced dissipation of the survival/longevity gene product).

One aspect of the present embodiments thus relates to the use of resveratrol and resveratrol-containing compositions to modulate gene expression, and in particular, to modulate the expression of “survival/longevity” genes and/or “damage inducing” genes. As used herein, a compound is said to “modulate” gene expression if its administration results in a change in expression (relative to a control) of such genes of at least 10%. Modulation may involve an increase in expression (“up-regulation”) or it may involve a decrease in expression (“down-regulation”). The term up-regulate thus denotes an increase of expression of at least 10%, at least 20%, at least 50%, at least 2-fold, at least 5-fold, or most preferably at least 10-fold (relative to a control). The term down-regulate conversely denotes a decrease of expression of at least 10%, at least 20%, at least 50%, at least 2-fold, at least 5-fold, or most preferably at least 10-fold (relative to a control).

A second aspect of the present embodiments relates to the use of resveratrol and resveratrol-containing compositions to modulate the concentration or activity of expressed products of “survival/longevity” genes and/or “damage inducing” genes. As used herein, a compound is said to “modulate” the concentration or activity of such expressed products if its administration results in a change in an intracellular, intercellular or tissue concentration or activity (relative to a control) of such gene products of at least 10%. Modulation may, for example, involve an “enhanced accumulation” or an “enhanced activity” or, for example, it may involve a “diminished accumulation” or a “diminished activity.” The term “enhanced accumulation” (or “enhanced activity”) denotes an increase in concentration (or activity) of at least 10%, at least 20%, at least 50%, at least 2-fold, at least 5-fold, or most preferably at least 10-fold (relative to a control). The term “diminished accumulation” or “diminished activity.” conversely denotes a decrease in concentration (or activity) of at least 10%, at least 20%, at least 50%, at least 2-fold, at least 5-fold, or most preferably at least 10-fold (relative to a control).

As used herein, a “survival/longevity” gene is a gene whose expression contributes to an increase in the survival or longevity of a subject (e.g., a mammal, and particularly a human) expressing such gene. Conversely, a “damage inducing” gene is a gene whose expression contributes to DNA, cellular, or tissue damage in such subject. Such genes are responders to biological stressors, they initiate action in response to stressors such as radiation (e.g., sunlight, gamma rays, UV light, etc.), radiomimetic agents (e.g., vitamin D), heat, near starvation (calorie restriction, or its mimetic, resveratrol) by modulating their expression.

In a preferred embodiment, the survival/longevity gene is a sirtuin gene. The sirtuins are a conserved family of deacetylases and mono-ADP-ribosyltransferases, which have emerged as key regulators of cell survival and organismal longevity. Mammals have at least seven sirtuins, including Sirtuins 1 through 7. Sirtuin 1 is a nuclear deacetylase that regulates functions including glucose homeostasis, fat metabolism and cell survival. The Sirtuin 1 gene is known to control the rate of aging of living organisms by virtue of its ability to produce DNA repair enzymes and mimics the beneficial effects of calorie restriction. The trans form of resveratrol (but not cis-resveratrol) activates the Sirtuin 1 gene. The Sirtuin 3 gene is a mitochondrial sirtuin that regulates acetyl-CoA synthetase 2, and thus its modulation has physiological applications including increasing mitochondrial biogenesis or metabolism, increasing fatty acid oxidation, and decreasing reactive oxygen species. The role of Sirtuin 3 in promoting cell survival during genotoxic stress was demonstrated in U.S. Patent Application Publication No. 2011/0082189. Preferred embodiments particularly pertain to compositions that modulate (increase or decrease) the concentration of the Sirtuin 1 or Sirtuin 3 survival/longevity gene products, particularly as compared to the ability of resveratrol alone to modulate the gene products.

In particular, commercial formulations (sold as Longevinex®) of the present embodiments have been shown to upregulate Sirtuin 3 at rates up to 2.95 times greater than resveratrol alone. Mukherjee et al., Can. J. Pharmol. Physiol. 2010 November; 88(11):1017-25. Sirtuin3 protein regulates manganese superoxide dismutase (Mn SOD) within the mitochondria, which may have direct affect upon aging, function and survival of the mitochondria with advancing age and in states of disease. Data also suggests that the commercial Longevinex® formulations lowered C-reactive protein (marker of inflammation), reduced insulin, raised HDL cholesterol and abolished impairment of flow-mediated arterial dilatation, the first sign of atherosclerotic disease.

Examples of survival/longevity genes and genes whose expression enhances cellular damage include, e.g., the genes disclosed in Tables 1 and 2, respectively. Most preferably, such genes are human genes.

TABLE 1 Exemplary Survival/Longevity Genes 39329, 39340, 0610007C21Rik, 0610007L01Rik, 0610010F05Rik, 0610037L13Rik, 0610037P05Rik, 0610040B10Rik, 0610042E11Rik, 1110001A07Rik, 1110002B05Rik, 1110003O08Rik, 1110005A03Rik, 1110007L15Rik, 1110007M04Rik, 1110008F13Rik, 1110008J03Rik, 1110008P14Rik, 1110014K08Rik, 1110018J18Rik, 1110019J04Rik, 1110020G09Rik, 1110028A07Rik, 1110028C15Rik, 1110032E23Rik, 1110033M05Rik, 1110036O03Rik, 1110038B12Rik, 1110038D17Rik, 1110054O05Rik, 1110058L19Rik, 1110059E24Rik, 1110059G10Rik, 1110067D22Rik, 1190017O12Rik, 1300010M03Rik, 1300012G16Rik, 1500002I01Rik, 1500002O20Rik, 1500005K14Rik, 1500011B03Rik, 1500011K16Rik, 1500031L02Rik, 1500034J01Rik, 1600012F09Rik, 1600015H20Rik, 1600027N09Rik, 1700001O22Rik, 1700011B04Rik, 1700017H01Rik, 1700020C11Rik, 1700021C14Rik, 1700021F05Rik, 1700023D09Rik, 1700029F09Rik, 1700029M20Rik, 1700030K09Rik, 1700040L02Rik, 1700051A21Rik, 1700113I22Rik, 1700127D06Rik, 1810007M14Rik, 1810011O10Rik, 1810012P15Rik, 1810013L24Rik, 1810015C04Rik, 1810020D17Rik, 1810021J13Rik, 1810022K09Rik, 1810026B05Rik, 1810029B16Rik, 1810030N24Rik, 1810034K20Rik, 1810035L17Rik, 1810044A24Rik, 1810049H13Rik, 1810058I24Rik, 1810059G22Rik, 1810063B05Rik, 1810073N04Rik, 2010106G01Rik, 2010109N14Rik, 2010111I01Rik, 2010200O16Rik, 2010305A19Rik, 2010309E21Rik, 2010315B03Rik, 2010320M18Rik, 2010321M09Rik, 2210010L05Rik, 2210020M01Rik, 2210408I21Rik, 2310001A20Rik, 2310002L09Rik, 2310007O11Rik, 2310011J03Rik, 2310014D11Rik, 2310014F07Rik, 2310016C16Rik, 2310026E23Rik, 2310030G06Rik, 2310033F14Rik, 2310036O22Rik, 2310038H17Rik, 2310042E22Rik, 2310043N10Rik, 2310044H10Rik, 2310046A06Rik, 2310047A01Rik, 2310047H23Rik, 2310047M10Rik, 2310061J03Rik, 2310067B10Rik, 2310076G13Rik, 2410001C21Rik, 2410002O22Rik, 2410003K15Rik, 2410004B18Rik, 2410005O16Rik, 2410012H22Rik, 2410017P07Rik, 2410017P09Rik, 2410018C17Rik, 2410018C20Rik, 2410019A14Rik, 2410022L05Rik, 2410042D21Rik, 2510003E04Rik, 2510042H12Rik, 2610001J05Rik, 2610008E11Rik, 2610019F03Rik, 2610024B07Rik, 2610028D06Rik, 2610029I01Rik, 2610030H06Rik, 2610101N10Rik, 2610200G18Rik, 2610209M04Rik, 2610301F02Rik, 2610507B11Rik, 2610528E23Rik, 2700029M09Rik, 2700038N03Rik, 2700097O09Rik, 2810004N23Rik, 2810008M24Rik, 2810410M20Rik, 2810422O20Rik, 2810423A18Rik, 2810430I11Rik, 2810455D13Rik, 2900002H16Rik, 2900006B11Rik, 2900008C10Rik, 2900011G08Rik, 2900024O10Rik, 3010003L21Rik, 3010027C24Rik, 3110003A17Rik, 3110031B13Rik, 3110043O21Rik, 3110073H01Rik, 3110080E11Rik, 3110082I17Rik, 3222402P14Rik, 3321401G04Rik, 4432414F05Rik, 4631424J17Rik, 4632404M16Rik, 4632411B12Rik, 4732416N19Rik, 4732418C07Rik, 4832420A03Rik, 4833408C14Rik, 4833439L19Rik, 4921506J03Rik, 4921509O07Rik, 4921513H07Rik, 4921517N04Rik, 4930402E16Rik, 4930426L09Rik, 4930429B21Rik, 4930432L08Rik, 4930432O21Rik, 4930448F12Rik, 4930453O09Rik, 4930455C21Rik, 4930466F19Rik, 4930486A15Rik, 4930505O20Rik, 4930513N20Rik, 4930523C07Rik, 4930524O07Rik, 4930544L04Rik, 4930551A22Rik, 4930554H23Rik, 4930557J02Rik, 4930570C03Rik, 4930570E01Rik, 4930573O21Rik, 4930579G24Rik, 4932442K08Rik, 4933402C05Rik, 4933403F05Rik, 4933404K13Rik, 4933407I18Rik, 4933411K20Rik, 4933413C19Rik, 4933421A08Rik, 4933426M11Rik, 4933428L01Rik, 4933429D07Rik, 4933433P14Rik, 4933434E20Rik, 4933440H19Rik, 5033414K04Rik, 5033421C21Rik, 5033423K11Rik, 5033430J17Rik, 5330423I11Rik, 5330439A09Rik, 5430402E10Rik, 5430402P08Rik, 5430407P10Rik, 5730470L24Rik, 5730507A11Rik, 5730536A07Rik, 5730601F06Rik, 5830404H04Rik, 5830415L20Rik, 5830428H23Rik, 5830432E09Rik, 5830436I19Rik, 5830457O10Rik, 5830469G19Rik, 5830487K18Rik, 5930434B04Rik, 6230429P13Rik, 6330403M23Rik, 6330407G11Rik, 6330409N04Rik, 6330415G19Rik, 6330417G04Rik, 6330503C03Rik, 6330564D18Rik, 6330569M22Rik, 6430548M08Rik, 6530404N21Rik, 6530413G14Rik, 6620401M08Rik, 6720462K09Rik, 6720475J19Rik, 6820401H01Rik, 7030402D04Rik, 7030407E18Rik, 7420416P09Rik, 8030463A06Rik, 8030475D13Rik, 8430436O14Rik, 9030411M15Rik, 9030418K01Rik, 9030425P06Rik, 9130011J15Rik, 9230110F11Rik, 9230114K14Rik, 9330109K16Rik, 9330120H11Rik, 9430010O03Rik, 9430013L17Rik, 9530018H14Rik, 9530018I07Rik, 9530097N15Rik, 9930024M15Rik, A030007L17Rik, A230046K03Rik, A230051G13Rik, A230062G08Rik, A230067G21Rik, A230091C14Rik, A330043J11Rik, A330076H08Rik, A430005L14Rik, A430102J17Rik, A430110N23Rik, A530082C11Rik, A730008L03Rik, A830018L16Rik, A930001N09Rik, A930006D11Rik, A930018M24Rik, A930026I22Rik, Ahcyl1, Amd1, Ank, Arhgap18, Arhgap20, Arhgap24, Arhgap29, Arhgap4, Arhgap5, Arhgap9, Arhgdia, Arhgef1, Arhgef12, Arhgef17, Arhgef2, B230117O15Rik, B230118H07Rik, B230219D22Rik, B230312A22Rik, B230337E12Rik, B230380D07Rik, B3galnt2, B630005N14Rik, B830007D08Rik, B830028B13Rik, B930093H17Rik, C030002C11Rik, C030007I01Rik, C030044B11Rik, C030046101Rik, C130057M05Rik, C130065N10Rik, C230091D08Rik, C430003N24Rik, C730025P13Rik, Cdc73, Col10a1, Col19a1, Col1a1, Col1a2, Col23a1, Col27a1, Col4a3bp, Col5a1, Col6a2, D030011O10Rik, D030051N19Rik, D230019N24Rik, D330001F17Rik, D330017J20Rik, D430015B01Rik, D430018E03Rik, D530037H12Rik, D630023B12Rik, D830046C22Rik, D930017J03Rik, D930020B18Rik, E030018N11Rik, E130014J05Rik, E130303B06Rik, E330021D16Rik, E430010N07Rik, E430018J23Rik, EG226654, EG622645, EG633640, ENSMUSG00000050599, ENSMUSG00000071543, ENSMUSG00000074466, ENSMUSG00000074670, ENSMUSG00000075401, Exdl1, G3bp1, Galnt3, Galnt4, Galnt14, Gart, Kcna5, Kcna7, Kcng2, Kcnj3, Kcnj5, Kcnk3, Kcnv2, Kctd10, Kctd2, Kctd7, LOC100044376, LOC100044968, LOC100045002, LOC100045020, LOC100045522, LOC100045629, LOC100046086, LOC100046343, LOC100046855, LOC100047028, LOC100047385, LOC100047539, LOC100047601, LOC100047794, LOC100047915, LOC100048376, LOC100048397, LOC100048439, LOC100048863, LOC640441, LOC668206, LOC675709, LOC677447, Mtm1, OTTMUSG00000001305, OTTMUSG00000016644, P2ry5, P2ry6, Pabpc3, Pah, Paics, Paip1, Paip2, Palm, Papd1, Papd5, Papola, Papolg, Paqr7, Paqr9, Pard3, Pard6g, Parp12, Pbef1, Pbld, Pbrm1, Pcbp2, Pcca, Pcdh7, Pcdh9, Pcgf3, Pcgf6, Pcm1, Pcmt1, Pcnt, Pcnx, Pcp4, Pcp4l1, Pcsk7, Pctk1, Pctk2, Pctk3, Pdcd10, Pdcd4, Pdcd6, Pdcl, Pdcl3, Pde1a, Pde2a, Pde4dip, Pde6a, Pde7a, Pdgfa, Pdha1, Pdia3, Pdia6, Pdk4, Pdlim4, Pdlim5, Pds5b, Pdss1, Pdxk, Pdzd11, Pecam1, Pef1, Per1, Per3, Perp, Pex11c, Pex12, Pex19, Pex5, Pex6, Pex7, Pfdn1, Pfdn4, Pfdn5, Pfkp, Pfn2, Pgam2, Pgbd5, Pggt1b, Pgr, Phc2, Phc3, Phf14, Phf17, Phf2011, Phf3, Phf6, Phka2, Phkb, Phkg1, Phlda1, Phldb1, Phpt1, Phyh, Pias4, Picalm, Pigz, Pik3ca, Pik3ip1, Pip5k1c, Pir, Pitpna, Pitpnb, Pitpnc1, Pitpnm1, Pkd1, Pkia, Pkm2, Pkp2, Pla2g10, Pla2g2d, Pla2g5, Plcd1, Plce1, Pld3, Pldn, Plec1, Plekhh3, Plekhj1, Plekhm2, Plekhn1, Plod3, Plp2, Pls3, Pltp, Plvap, Plxnb2, Pmm1, Pno1, Pnpla1, Pnpla2, Pnpla6, Pnrc2, Podn, Poldip3, Polg2, Polr2d, Polr2f, Polr2h, Polr2i, Polr2k, Polr3gl, Polr3k, Pot1a, Pou6f1, Ppap2b, Ppard, Pparg, Ppargc1a, Pphln1, Ppic, Ppif, Ppig, Ppil2, Ppl, Ppm1f, Ppme1, Ppp1ca, Ppp1r11, Ppp1r12a, Ppp1r12c, Ppp1r13l, Ppp1r2, Ppp1r3c, Ppp2ca, Ppp2r2d, Ppp2r3c, Ppp2r5c, Ppp4r11, Ppp5c, Ppp6c, Ppt2, Pq1c1, Prdm4, Prdm5, Prdx2, Prdx3, Preb, Prei4, Prkab2, Prkaca, Prkcbp1, Prkcdbp, Prkch, Prkcn, Prkcsh, Prkcz, Prkrir, Prlr, Prmt7, Prodh, Prosc, Prpf6, Prpsap1, Prr12, Prrc1, Prss12, Prune, Psap, Pscd1, Psd3, Psenen, Pskh1, Psma2, Psma5, Psma6, Psma8, Psmb7, Psmd11, Psmd12, Psmd4, Psmd6, Psmd8, Pstk, Ptdss2, Ptgfrn, Ptms, Ptp4a3, Ptpla, Ptpn1, Ptpn11, Ptpn12, Ptpn20, Ptpn3, Ptpra, Ptprg, Ptprs, Pttg1, Puf60, Pum1, Pus1, Pxmp3, Pxn, Qk, Rab1, Rab11a, Rab11b, Rab2, Rab20, Rab21, Rab24, Rab30, Rab33b, Rab35, Rab3a, Rab3gap1, Rab3gap2, Rab3il1, Rab43, Rab6, Rab8b, Rabep1, Rabgap11, Rac1, Rad17, Rad23b, Rad54l2, Rag1ap1, Ralgps2, Ramp2, Ranbp10, Ranbp2, Rap1a, Rap1gap, Rap2a, Rap2b, Raph1, Rara, Rarb, Rarg, Rasa1, Rasa3, Rasl2-9, Rassf7, Rb1cc1, Rbbp6, Rbj, Rbm12, Rbm20, Rbm24, Rbm27, Rbm28, Rbm38, Rbm39, Rbms1, Rbms2, Rbmxrt, Rbpms, Rcan2, Rcl1, Rdh13, Reep5, Rem2, Retsat, Rev1, Rfc2, Rfc4, Rfesd, Rfng, Rfwd3, Rfx1, Rgl1, Rgma, Rgs12, Rgs5, Rhbdd2, Rhbdd3, Rhbdf1, Rhd, Rhobtb1, Rhobtb2, Rhoq, Ric8, Ring1, Rlbp1, Rmnd1, Rmnd5b, Rnaset2a, Rnd1, Rnf11, Rnf13, Rnf139, Rnf14, Rnf149, Rnf167, Rnf168, Rnf187, Rnf2, Rnf31, Rnf34, Rnf5, Rnf6, Rock1, Rorc, RP23-136K12.4, rp9, Rpap2, Rpe, Rpl15, Rpl27a, Rpl37, Rpl39, Rpl31, Rpl711, Rpl8, Rplp2, Rpo1-3, Rpo1-4, Rpp30, Rprml, Rps11, Rps26, Rps6, Rps6ka1, Rps6ka4, Rrad, Rragc, Rragd, Rras2, Rrbp1, Rrp1, Rrp9, Rsad1, Rspry1, Rtp3, Rufy1, Rufy3, Rusc1, Rwdd1, Rxrb, Rxrg, Ryk, Ryr2, S3-12, Sae2, Safb, Samd5, Samd8, Samd9l, Saps3, Sar1a, Sars, Sat1, Satb2, Sbds, Sbf2, Sbk1, Sc4mol, Scamp3, Scap, Scara5, Scarb1, Scarb2, Sccpdh, Scfd1, Schip1, Scmh1, Scn4b, Scoc, Scube2, Scyl1, Scyl3, Sdcbp, Sdccag10, Sdha, Sdhd, Sds, Sec11a, Sec14l1, Sec22b, Sec23a, Sec31a, Sec61a1, Sec61a2, Sele, Sema3b, Sephs2, Sepp1, Serbp1, Serinc1, Serpinb6a, Serpinb9, Sertad2, Set, Setd7, Setd8, Setx, Sf3a1, Sf3b1, Sf3b2, Sfrp5, Sfrs1, Sfrs10, Sfrs2ip, Sfrs7, Sfrs9, Sfxn3, Sgca, Sgcg, Sgk2, Sgta, Sh2d3c, Sh2d4a, Sh3bgrl, Sh3bp5l, Sh3d19, Sh3kbp1, Shb, Shmt2, Shroom3, Sirt1, Skil, Skiv2l2, Slain2, Slc10a1, Slc12a4, Slc12a5, Slc16a1, Slc16a4, Slc1a5, Slc1a6, Slc20a1, Slc22a17, Slc22a5, Slc25a11, Slc25a12, Slc25a17, Slc25a22, Slc25a28, Slc25a3, Slc25a32, Slc25a33, Slc25a34, Slc25a36, Slc25a4, Slc25a42, Slc25a46, Slc26a11, Slc27a1, Slc29a1, Slc31a1, Slc35a2, Slc35a3, Slc35b1, Slc35b2, Slc36a2, Slc39a1, Slc39a10, Slc39a8, Slc40a1, Slc44a1, Slc47a1, Slc4a2, Slc4a4, Slc4a7, Slc6a19, Slc6a6, Slc6a9, Slc7a1, Slc7a4, Slc7a7, Slc9a1, Slco1a4, Slco3a1, Slco5a1, Slit3, Slmap, Slmo2, Smarca2, Smarcc2, Smarcd3, Smchd1, Smcr7, Smn1, Smndc1, Smoc2, Smpd1, Smpdl3a, Smtn, Smtnl2, Smu1, Smurf1, Smyd1, Smyd4, Snapap, Snapc1, Snfllk2, Snora65, Snrk, Snrp70, Snrpb2, Snrpd3, Snx12, Snx13, Snx16, Socs3, Socs4, Sorbs1, Sorcs2, Sort1, Sost, Sox17, Sox4, Sox9, Sp3, Spag9, Spcs1, Speer7-ps1, Spg3a, Spg7, Spin1, Spink10, Spna2, Spnb1, Spnb2, Spop, Spry2, Sqstm1, Srd5a2l2, Srebf1, Srebf2, Sri, Srl, Srp19, Srpr, Ssbp3, Ssbp4, Ssh1, Ssr3, Sstr5, Ssu72, St13, St3gal6, St6galnac6, St7, St8sia2, St8sia4, Stab1, Stard10, Stat6, Stbd1, Stch, Stip1, Stk11, Stk19, Stk38, Stk39, Stom, Strn3, Stx6, Stxbp2, Styx, Suhw3, Sulf2, Supt5h, Supv3l1, Surf4, Svep1, Sybl1, Syk, Syn2, Syngr2, Synj2bp, Synpo, Syp1, Taf2, Taf6, Tanc1, Taok2, Taok3, Tap1, Tap2, Tapt1, Tardbp, Tatdn3, Tbc1d10b, Tbc1d15, Tbc1d19, Tbc1d20, Tbc1d2b, Tbc1d5, Tbc1d7, Tbcb, Tbcc, Tbce, Tbcel, Tbkbp1, Tbpl1, Tbx19, Tbx20, Tcap, Tcea1, Tcea3, Tcf15, Tcf20, Tcf25, Tcfe2a, Tcof1, Tcp1, Tcp11l2, Tcta, Tead4, Tef, Tesk1, Tex2, Tex261, Tfam, Tfb2m, Tfpi, Tfrc, Tgds, Tgfbr1, Thbs4, Thnsl2, Thoc1, Thoc4, Thrb, Tie1, Tigd2, Timm22, Timm50, Timp3, Timp4, Tinagl, Tjap1, Tk2, Tle6, Tlk2, Tln1, Tloc1, Tm2d1, Tm2d2, Tm2d3, Tm4sf1, Tm6sf2, Tm9sf2, Tm9sf3, Tmc1, Tmcc1, Tmcc3, Tmco1, Tmed7, Tmem103, Tmem109, Tmem110, Tmem112b, Tmem115, Tmem119, Tmem123, Tmem126b, Tmem132a, Tmem142a, Tmem142c, Tmem147, Tmem14c, Tmem157, Tmem159, Tmem167, Tmem168, Tmem16f, Tmem176a, Tmem176b, Tmem182, Tmem188, Tmem19, Tmem30a, Tmem37, Tmem38a, Tmem38b, Tmem41a, Tmem41b, Tmem46, Tmem50a, Tmem55b, Tmem57, Tmem64, Tmem69, Tmem70, Tmem77, Tmem85, Tmem86a, Tmem93, Tmem9b, Tmlhe, Tmod1, Tmod4, Tmub1, Tmub2, Tnfaip1, Tnfaip8l1, Tnfrsf11a, Tnfrsf18, Tnfrsf1a, Tnfsf5ip1, Tnip1, Tnks1bp1, Tnni3, Tnni3k, Tnnt2, Tnpo1, Tnpo2, Tnrc6a, Tns4, Tnxb, Toe1, Tollip, Tomm22, Tomm34, Tomm40, Tomm70a, Top1, Top2b, Topors, Tor1aip2, Tpcn1, Tpm1, Tpm3, Tpm4, Tpp1, Tpp2, Tppp3, Tpr, Tprkb, Tpst1, Traf3ip2, Traip, Trak2, Trappc2, Trappc21, Trem3, Trex1, Trim11, Trim12, Trim23, Trim26, Trim29, Trim3, Triobp, Trip4, Trmt11, Tro, Troap, Trpc1, Trpc4ap, Trpm4, Tsc22d1, Tsc22d4, Tsfm, Tsga10, Tsnax, Tspan13, Tspan18, Tspan4, Tspan7, Tssc4, Tsta3, Ttc1, Ttc28, Ttc32, Ttc33, Ttc35, Ttc9c, Tub, Tuba4a, Tuba8, Tubb2c, Tubb5, Tufm, Tug1, Tulp4, Twsg1, Txlna, Txlnb, Txndc1, Txndc10, Txndc12, Txndc14, Txndc4, Txnip, Txnl1, Txnl4, Txnl4b, Tyk2, Uaca, Ubac1, Ubap1, Ubash3a, Ubd, Ube1c, Ube112, Ube1x, Ube2b, Ube2d2, Ube2d3, Ube2e1, Ube2f, Ube2h, Ube2n, Ube2o, Ube2q2, Ube2v1, Ube2v2, Ube2w, Ube3a, Ubl4, Ubl7, Ublcp1, Ubtf, Ubxd7, Uchl5, Ucp2, Ucp3, Ufm1, Ugcgl2, Ugp2, Umps, Ung, Unk, Uqcc, Uqcrc1, Uqcrfs1, Usp11, Usp19, Usp2, Usp21, Usp22, Usp34, Usp36, Usp45, Usp47, Usp52, Usp54, Usp9y, Utp6, Utrn, Uvrag, Uxt, V1ra5, Vamp4, Vasn, Vbp1, Vdac1, Vdac2, Vdac3, Vdp, Vegfa, Vegfb, Vegfc, Vezf1, Vkorc111, Vldlr, Vps16, Vps18, Vps29, Vps35, Vps36, Vps37b, Vps4b, Vps54, Vwf, Wac, Wapal, Was, Wbp4, Wdfy1, Wdr13, Wdr21, Wdr22, Wdr23, Wdr3, Wdr47, Wdr5b, Wdr92, Wdsof1, Wfdc3, Wipi2, Wnk1, Wtap, Wwp2, Xbp1, Xdh, Xlr5a, Xpnpep1, Xpr1, Xrcc1, Xrcc6, Yap1, Yeats2, Yif1a, Yipf3, Yipf4, Yipf7, Ypel2, Ypel3, Ywhaq, Zadh1, Zbed3, Zbtb43, Zbtb5, Zc3h11a, Zc3h12c, Zc3h15, Zc3h6, Zc3h8, Zcchc6, Zdhhc13, Zdhhc3, Zeb1, Zfand5, Zfml, Zfp106, Zfp110, Zfp187, Zfp191, Zfp213, Zfp236, Zfp238, Zfp26, Zfp260, Zfp277, Zfp289, Zfp30, Zfp313, Zfp319, Zfp322a, Zfp335, Zfp341, Zfp35, Zfp383, Zfp384, Zfp414, Zfp422, Zfp422-rs1, Zfp512, Zfp516, Zfp560, Zfp568, Zfp579, Zfp597, Zfp608, Zfp628, Zfp629, Zfp639, Zfp644, Zfp650, Zfp651, Zfp667, Zfp672, Zfp68, Zfp703, Zfp715, Zfp719, Zfp740, Zfp758, Zfp817, Zfp82, Zfyve21, Zhx2, Zhx3, Zic2, Zkscan17, Zmat2, Zmat5, Zmym4, Zmynd10, Znrf1, Zrsr1, Zscan12, Zswim6, Zyg11b, Zyx, Zzef1

TABLE 2 Exemplary Genes Whose Expression Enhances Cellular Damage AA407175, AA415038, AA987161, Aadacl1, Aars, Aasdhppt, AB182283, Abca4, Abca7, Abcb4, Abcb7, Abcd1, Abce1, Abhd1, Abhd12, Abhd4, Abi1, Abi2, Ablim2, Abra, Abtb1, Acaa2, Acad11, Acad9, Acadl, Acads, Acadvl, Acbd3, Acbd5, Acbd6, Ace, Aco2, Acot5, Acox3, Acsl1, Acss2, Acta1, Actb, Actn1, Actn2, Actn4, Actr1b, Actr2, Acvr1b, Acvr2a, Acvrl1, Acyp1, Acyp2, Adal, Adam10, Adam15, Adam21, Adamts10, Adamts2, Adamts7, Adamts9, Adar, Adcy1, Adcy2, Adcy3, Adcy6, Add1, Adh5, Adra1b, Adrbk1, Aebp1, Aes, Afap111, Aff4, Afg3l1, Aga, Agbl5, Agpat1, Agpat5, Agrn, Agtr1a, Agxt2l2, Ahdc1, Ahr, Ahsa1, AI118078, AI225934, AI413194, AI428479, AI429363, AI462493, AI480535, AI506816, AI597468, AI662270, AI662476, AI747699, AI790298, AI837181, AI848100, AI852064, AI987944, Ak7, Akap13, Akap2, Akp2, Akr1a4, Akr1b8, Akr7a5, Akt1s1, Alas1, Aldh1a3, Aldh2, Aldh4a1, Aldh7a1, Aldh9a1, Alg12, Alg13, Alg5, Alkbh6, Alkbh8, Als2cr2, Anapc10, Anapc2, Angptl2, Ank1, Ankhd1, Ankrd1, Ankrd10, Ankrd13a, Ankrd13c, Ankrd13d, Ankrd25, Ankrd28, Ankrd32, Ankrd37, Ankrd38, Ankrd9, Anp32b, Anxa3, Anxa6, Aoc3, Ap1s2, Ap2a2, Ap2b1, Ap2m1, Ap4m1, Ap4s1, Apbb1, Aplp2, Apobec2, Apod, Apoe, Apool, Appl1, Appl2, Arf1, Arf3, Arg2, Arid4b, Arl1, Arl2bp, Arl3, Arl4a, Arl5b, Arpc1a, Arpc1b, Arpc2, Arpc4, Arrb1, Art5, Asb1, Asb14, Asb5, Ascc3l1, Asnsd1, Asph, Atad2b, Atf3, Atg10, Atg3, Atg4d, Atg5, Atp11b, Atp13a1, Atp1a2, Atp5h, Atp5s, Atp6ap2, Atp6v0a2, Atp6v0d1, Atp6v1b2, Atp6v1f, Atp9a, Atp9b, Atpaf1, Atpbd1c, Atpif1, Atr, Atxn2, Atxn7l1, AU020772, AU041133, Aup1, AV009015, AV024533, AV025504, Avpr1a, AW046287, AW112010, AW209491, AW555464, AW556556, AW742931, Azi2, Azin1, Bach1, Bag4, Bambi, Banp, Bat1a, Bat2, Baz1a, Baz1b, BB217526, Bbc3, Bbs10, BC003331, BC003885, BC003965, BC010304, BC010981, BC011248, BC013529, BC016495, BC019943, BC020077, BC021395, BC023882, BC024659, BC024814, BC025076, BC028440, BC028528, BC030183, BC030308, BC030336, BC031353, BC031781, BC032203, BC034069, BC037034, BC037112, BC038479, BC039210, BC043098, BC043476, BC048679, BC049349, BC057893, Bcam, Bcat2, Bckdha, Bckdk, Bcl2l13, Bcl6b, Bclaf1, Bdp1, Bet1, Bgn, Bhlhb2, Bhlhb3, Bicd2, Birc4, Blvra, Bmi1, Bmp6, Bmpr1a, Bnip3, Brd3, Btaf1, Btbd14b, Btbd2, Btbd3, Btbd6, Btf3l4, Btnl9, Bxdc2, C130094E24, C2, C77058, C78441, C78651, C79741, C86942, C87259, Cab39, Cabin1, Cacna1g, Cacna1h, Cacybp, Cadm4, Calm1, Calr, Calr3, Caml, Camsap1, Cand2, Canx, Capg, Capn1, Capns1, Caprin1, Card10, Caskin2, Casp8ap2, Casp9, Casq1, Cav1, Cav2, Cbfb, Cblb, Cbr1, Cbx3, Ccar1, Ccdc12, Ccdc122, Ccdc125, Ccdc127, Ccdc3, Ccdc34, Ccdc47, Ccdc58, Ccdc69, Ccdc7, Ccdc72, Ccdc85b, Ccdc88a, Ccdc90a, Ccdc90b, Ccl9, Ccm2, Ccnd3, Ccng1, Ccnh, Ccni, Ccnl2, Ccnt2, Ccr1, Ccr1l1, Ccr5, Ccs, Cct5, Cct7, Cd151, Cd163, Cd200, Cd207, Cd36, Cd38, Cd74, Cd83, Cd93, Cd97, Cdadc1, Cdc27, Cdc2l5, Cdc2l6, Cdc37, Cdc42ep3, Cdgap, Cdh13, Cdipt, Cdk5rap3, Cdk7, Cdv3, Cebpz, Cenpa, Cenpq, Centa1, Centa2, Centb2, Centd1, Centd2, Centg2, Cetn3, Cfl1, Cflar, Cgnl1, Cgrrf1, Chac1, Chac2, Chchd4, Chd1, Chd2, Chd4, Chmp1b, Chmp2b, Chordc1, Chrac1, Chrd, Chrng, Chst14, Chuk, Churc1, Ciao1, Cib1, Cic, Cilp2, Cisd2, Cish, Ckm, Ckmt2, Clcn5, Cldnd1, Clec2d, Clic1, Clic4, Clint1, Clk3, Cln5, Clock, Clptm1, Clstn1, Cltc, Cmpk, Cmya5, Cndp2, Cnot6l, Cnot7, Cntfr, Cntn4, Commd1, Commd3, Commd4, Commd5, Comp, Cope, Copg, Cops2, Cops7a, Coq10b, Coq9, Coro1b, Cox11, Cox4i2, Cox5a, Cox8a, Cp, Cpeb4, Cpm, Cpsf1, Cpsf3, Cpt1a, Cpt1b, Cramp1l, Crat, Crbn, Creb1, Creb3l1, Crebbp, Crebzf, Creg1, Crip1, Crip2, Cript, Crnkl1, Crot, Cry1, Cryab, Crybb1, Cryz, Csdc2, Cse1l, Csf2ra, Csl, Csnk1a1, Csnk1d, Csnk2a1, Cst3, Cst8, Cstf2, Ctage5, Ctcf, Ctgf, Ctps, Ctsb, Ctsf, Ctss, Ctsz, Cttnbp2nl, Cul1, Cul3, Cxcl12, Cxcl14, Cxxc1, Cxxc5, Cyb561, Cyb5b, Cyb5r3, Cyb5r4, Cybasc3, Cyc1, Cyfip1, Cyp1b1, Cyp27a1, Cyp2f2, Cys1, D030063E12, D0H4S114, D10Ertd641e, D13Ertd787e, D14Ertd16e, D14Ertd581e, D15Ertd50e, D16H22S680E, D19Ertd721e, D19Ertd737e, D19Wsu162e, D1Bwg1363e, D2Ertd391e, D3Ertd254e, D3Wsu106e, D4Ertd429e, D4Ertd571e, D6Wsu176e, D8Ertd457e, D8Ertd54e, D8Ertd620e, D8Ertd82e, D9Ertd402e, Daam1, Dad1, Dap, Dapk2, Daxx, Dbh, Dcn, Dctn1, Dctn2, Dcun1d1, Dcun1d2, Dcun1d5, Ddah2, Ddb1, Ddb2, Ddit3, Ddr1, Ddr2, Ddx1, Ddx17, Ddx39, Ddx51, Ddx54, Ddx58, Ddx6, Deb1, Dedd, Defb1, Defb5, Defcr15, Depdc7, Derl2, Des, Dfna5h, Dgat2, Dgcr2, Dgka, Dgke, Dguok, Dhodh, Dhrs1, Dhrs7, Dhx30, Dhx32, Dhx34, Dhx8, Dhx9, Diablo, Diap1, Diras1, Dirc2, Dkk3, Dld, Dll4, Dlst, Dmd, Dmpk, Dmtf1, Dmwd, Dmxl2, Dnahc9, Dnaja3, Dnajb1, Dnajb4, Dnajb9, Dnajc12, Dnajc3a, Dnajc7, Dnm2, Dock11, Dock6, Dom3z, Dopey1, Dot11, Dpagt1, Dph3, Dpp8, Dpp9, Dpysl2, Dpysl3, Dr1, Drg1, Dstn, Dtnbp1, Dus3l, Dusp1, Dusp6, Dusp8, Dvl2, Dync1h1, Dync1li2, Dyrk1a, E2f6, Eaf1, Eapp, Ears2, Ebag9, Ece1, Ecm1, Ecm2, Edaradd, Edg3, Eea1, Eef1a1, Eef1b2, Eef1e1, Eef2, Efcab2, Efemp2, Efnb3, Egf, Egfl7, Egflam, Egfr, Egln1, Egln3, Egr1, Ehbp1l1, Ehd4, Ei24, Eif1ay, Eif2ak1, Eif2s2, Eif3e, Eif4a1, Eif4a2, Eif4b, Eif4e2, Eif4ebp1, Eif4g3, Eif5, Eif5b, Elac2, Elf2, Elk3, Ell, Ell2, Elovl5, Elp3, Elp4, Eltd1, Emb, Emd, Eme2, Emg1, Emilin1, Eml2, Enc1, Eng, Eno3, Enpep, Enpp5, Entpd5, Entpd6, Ep300, Epb4.1l3, Epha4, Ephb1, Ephb4, Epm2aip1, Epn1, Eps15l1, Erc1, Ergic3, Erlin1, Ero1lb, Errfi1, Esco1, Esd, Esf1, Esrrg, Etfa, Etnk1, Ets2, Ewsr1, Exoc5, Exosc1, Exosc10, Exosc7, Exosc9, Ext1, Eya3, F11r, F13b, F5, Fads3, Fahd2a, Fam18b, Fancg, Fap, Fas, Fastkd1, Fastkd2, Fbln1, Fbln2, Fbp2, Fbxl2, Fbxl6, Fbxo3, Fbxo30, Fbxw4, Fbxw5, Fcer2a, Fcgr4, Fdx1, Fem1c, Fert2, Fgfr1op, Filip1, Fkbp10, Fkbp5, Fkbp8, Flcn, Flii, Flot1, Flot2, Flywch1, Fmn1, Fmo2, Fmr1, Fnbp1l, Fnip1, Foxa3, Foxj2, Foxk1, Foxk2, Foxo1, Foxp1, Frag1, Frap1, Frmd4b, Frmd5, Fscn1, Fth1, Ftl1, Fuca2, Fundc2, Furin, Fus, Fxc1, Fxyd1, Fxyd5, Fzd10, Fzd2, Fzd9, G0s2, G6pc2, Gaa, Gab1, Gabpa, Gadd45b, Gadd45g, Gale, Galk1, Gapdh, Gapvd1, Garnl1, Gas6, Gata4, Gba2, Gbas, Gbe1, Gbf1, Gcdh, Gdi1, Gdi2, Gdpd1, Gdpd5, Gemin5, Ggta1, Ghitm, Gimap4, Gimap8, Git1, Gja3, Gle1l, Glg1, Gli1, Glo1, Glod4, Gls, Gltscr2, Glud1, Glul, Gm104, Gm561, Gmeb1, Gmfb, Gmppa, Gna-rs1, Gnb2, Gnb4, Gne, Gng10, Gnl3, Gnpda1, Golga2, Golga7, Golgb1, Got1, Got2, Gpaa1, Gpam, Gpatch1, Gpbp1, Gpbp1l1, Gpc1, Gpc6, Gpd1l, Gper, Gpkow, Gpr115, Gpr137, Gpr175, Gpr22, Gpr4, Gpr98, Gpsn2, Gpt2, Gpx3, Gramd1a, Grb14, Grina, Grk1, Grk5, Grlf1, Grm8, Grn, Grpel2, Gsdmdc1, Gsn, Gsta4, Gstcd, Gstm1, Gstm2, Gstm5, Gstm7, Gstp1, Gstt1, Gtf2a1, Gtf2a2, Gtf2e1, Gtf2e2, Gtf2h3, Gtf2h4, Gtf3c1, Gtf3c4, Gtpbp1, Gtpbp2, Gulo, Gyg, Gyk, Gys1, H2afv, H2afy, H2-Bl, H2-Oa, H2-T24, H6pd, Hadh, Hadha, Hadhb, Hand2, Hars, Hars2, Hat1, Hax1, Hccs, Hcfc1r1, Hcfc2, Hdac2, Hdac4, Hdac7a, Hdhd2, Hdlbp, Heatr5b, Heatr6, Hectd1, Heph, Herpud1, Heyl, Hfe2, Hgs, Hhatl, Hiat1, Hiatl1, Hibadh, Hif1a, Higd1b, Hint3, Hirip3, Hivep2, Hk3, Hlf, Hmcn1, Hmg20b, Hmgb1, Hmgb3, Hmgcl, Hmgcs1, Hnrpab, Hnrph3, Hnrpk, Hnrpl, Hnrpll, Hnrpr, Hnrpul1, Hoxd11, Hrasls, Hrc, Hs2st1, Hsd17b11, Hsd17b13, Hsd17b4, Hsdl2, Hsp110, Hspa1b, Hspa5, Hspb2, Hspb3, Hspb6, Hspb7, Hspe1, Htra1, Htra3, Hus1, Hyal4, lah1, lbrdc2, ld1, Ide, Idh3a, Idh3b, Ifi30, Ifit3, Ifnar1, Ifnar2, Ifngr1, Ifngr2, Ift122, Ift57, Igfbp4, Igfbp6, Igsf11, Igsf3, Igsf8, Ihpk1, Ikbkap, Il10rb, Il13ra1, Il18bp, Il6st, Ilk, Ilvbl, Immp1l, Immp2l, Immt, Imp3, Impa2, Impad1, Ints8, Ipmk, Ipo13, Ipo7, Ipo8, Iqsec1, Iqwd1, Irf4, Irs1, Isca2, Isg20, Isyna1, Itfg3, Itgb1bp1, Itgb1bp2, Itgb1bp3, Itgb2, Itgb5, Itih3, Itk, Itm2b, Itm2c, Itpr3, Ivns1abp, Jam2, Jmjd1c, Jmjd2a, Jmjd6, Josd2, Jtv1, Jun, Kbtbd10, Kbtbd5, Kcnip2, Khk, Kif1b, Kif1c, Kif21a, Kif2a, Kif3a, Kif5b, Klc3, Klf11, Klf13, Klf15, Klf16, Klf4, Klf7, Klhdc1, Klhdc3, Klhl13, Klhl22, Klhl23, Klhl24, Klhl4, Klhl9, Klk1b24, Kpna1, Kpna4, Krr1, Kti12, Ktn1, L1cam, l7Rn6, Lace1, Lactb, Lama2, Lamb2, Laptm4a, Larp1, Larp2, Larp4, Larp5, Lcmt1, Lcmt2, Ldb1, Ldb3, Ldhb, Ldhd, Leo1, Lgals3bp, Lgals7, Lgmn, Lgr4, Lgr6, Lias, Limd1, Lims2, Lipe, Lix1l, Llgl1, Lmbrd1, Lmln, Lmna, Lmo4, Lmtk2, LOC100040515, LOC100043489, LOC100046468, LOC100046982, LOC552902, Lonp1, Lor, Lpgat1, Lphn1, Lrch1, Lrch4, Lrp10, Lrp2bp, Lrp6, Lrpap1, Lrrc1, Lrrc20, Lrrc39, Lrrc3b, Lrrc40, Lrrc44, Lsm14a, Lsm14b, Lsm3, Ltb4dh, Ltbp3, Ltbp4, Ly6a, Lypla1, Lypla2, Lyrm4, Lyrm5, Lysmd2, Lysmd3, Lztfl1, Lztr1, M6prbp1, Macf1, Macrod1, Maf1, Magea5, Magee1, Magi3, Mall, Man2b1, Maob, Map1lc3a, Map1lc3b, Map2k1ip1, Map2k2, Map3k1, Map3k12, Map3k2, Map3k7, Map3k7ip1, Map4k5, Mapbpip, Mapk14, Mapk6, Mapkapk2, Mapre1, Marcks, Mat2a, Mat2b, Matn4, Maz, Mbc2, Mbd2, Mbd3, Mbd5, Mboat5, Mbtps1, Mbtps2, Mcf2l, Mctp2, Mdfic, Mdh2, Med13, Med16, Med19, Med25, Med30, Med7, Mef2b, Mef2c, Mef2d, Megf11, Megf8, Mel13, Mertk, Mesdc2, Metrnl, Mett10d, Mex3c, Mfap4, Mfge8, Mfn1, Mfsd8, Mgam, Mgat1, Mgat4b, Mgp, Mgrn1, Mif4gd, Mkl1, Mknk1, Mlf1, Mlkl, Mll2, Mllt1, Mllt6, Mlx, Mlxip, Mlycd, Mme, Mmp15, Mmp1b, Mmp2, Mmrn2, Mobkl3, Mocos, Mocs2, Morc2a, Mosc2, Mospd1, Mpa2l, Mpp6, Mpv17, Mrfap1, Mrgprf, Mrpl1, Mrpl15, Mrpl17, Mrpl19, Mrpl28, Mrpl30, Mrpl32, Mrpl36, Mrpl38, Mrpl4, Mrpl41, Mrps17, Mrps18c, Mrps22, Mrps5, Mrs2l, Msl31, Msra, Msrb2, Msrb3, Msx1, Mtap4, Mtap7d1, Mtbp, Mtch2, Mterf, Mterfd1, Mterfd2, Mterfd3, Mtif3, Mtmr1, Mtmr3, Mtrr, Mustn1, Mxd4, Mxi1, Mxra8, Mybbp1a, Mybpc3, Myc, Mycbp, Myct1, Myd116, Myd88, Myef2, Myh14, Myh6, Myl4, Myl7, Mylip, Myo10, Myo1c, Myo9b, Myocd, Myom1, Mypn, N6amt1, N6amt2, Naca, Nagpa, Nars, Nat5, Nbeal1, Nckap1l, Ndst4, Ndufa5, Ndufab1, Ndufaf1, Ndufb3, Ndufb7, Ndufb8, Ndufc1, Ndufc2, Ndufs1, Ndufs2, Ndufs3, Ndufs5, Ndufs7, Ndufs8, Ndufv1, Ndufv2, Nedd4, Neil1, Nek3, Nf2, Nfu1, Ngly1, Ngrn, Nid1, Nif3l1, Ninj1, Nipbl, Nkiras1, Nkiras2, Nlgn2, Nmnat1, Npc1, Nppb, Nras, Nrd1, Nrp1, Nrp2, Nrtn, Nsmaf, Nt5c2, Nt5c3, Nub1, Nwd1, Oasl2, Ogg1, Oplah, Pfkfb2, Pfkfb4, Pgc1, Pgls, Pygb, Rars, Rars2, Rere, Rnpepl1, RP23-233B9.8, Rsrc2, Smad1, Smad3, Smad6, Ucp3, X83328, Xk, Xpo4, Xpo6, Xpot, Xrn1

Some embodiments provide a composition that comprises trans-resveratrol and a metal chelating agent, and may additionally comprise quercetin, one or more glycosaminoglycans, and/or vitamin D. The trans-resveratrol may be encapsulated to substantially preserve the biological activity of the composition from loss due to exposure of the trans-resveratrol to light or oxygen. Particularly provided are compositions that comprise resveratrol, a chelator, hyaluronic acid, and/or vitamin D, and compositions which comprise the chelator phytic acid (inositol hexaphosphate; IP6), the glycosaminoglycan hyaluronic acid, and vitamin D.

Other embodiments provide resveratrol-containing compositions capable of modulating gene expression to an extent greater than that observed with resveratrol alone or with calorie restriction. The compositions may be used to up-regulate a survival/longevity gene or down-regulate a gene whose expression enhances cellular damage upon administration to a recipient, and may also be used in the treatment or prevention of cancer, cardiovascular disease, diseases associated with aging, and other conditions and illnesses. Particular embodiments provide a resveratrol-containing composition that, upon administration to a recipient, modulates the concentration or activity, relative to resveratrol alone or calorie restriction, of the product of a survival/longevity gene or the product of a gene whose expression enhances cellular damage. Administration is preferably by oral ingestion.

The embodiments further particularly pertains to compositions that increase the concentration of the forkhead Foxo1 (daf-16, dFoxO) transcription factor survival/longevity gene product.

Particular embodiments provide compositions and methods where the modulation alters: (A) oxidative phosphorylation; (B) actin filament length or polymerization; (C) intracellular transport; (D) organelle biogenesis; (E) insulin signaling; (F) glycolysis; (G) gluconeogenesis; or (H) fatty acid metabolism. The gene product may be a survival/longevity gene product, and particularly Sirtuin 1, Sirtuin 3, or the forkhead Foxo1 transcription factor. The gene product may enhance cellular damage, and particularly may be encoded by the uncoupling protein 3, Pgc-1, or pyruvate dehydrogenase kinase 4 genes.

D. Packaging of the Compositions

Resveratrol is typically unstable to light and oxidation (Shaanxi University of Science & Technology, Xianyang China (2007) Zhong Yao Cai. 30(7):805-80). The resveratrol of the present embodiments is preferably prepared, packaged and/or stored in a manner that maximizes its specific activity. It is preferred to prepare, package and/or store resveratrol in low light (or in the dark) and/or in low oxygen, so as to minimize light-induced degradation (e.g., photo-isomerization) or oxygen-induced degradation. The preferred compositions of the present embodiments are formulated as dietary supplements for oral ingestion in the form of a pill, lozenge, capsule, elixir, syrup, etc. Other modalities of administration may alternatively be employed (e.g., intranasal, parenteral, intravenous, intraarterial, topical, etc.).

The resveratrol or plant extract comprising resveratrol is preferably encapsulated in a substantially oxygen-free environment. As used herein, the phrase “substantially oxygen-free” is intended to include environments having less than less than about 100 parts per million oxygen. Ideally, the encapsulation process would take place immediately after the extraction or formation of the small molecules and be shielded from exposure to light, heat, and oxygen. Alternatively, the material including small molecules may be stored in a substantially oxygen-free environment until encapsulated. The encapsulation process includes the steps of (1) providing a capsule including a head portion and a body portion; (2) at least partially filling the body portion with the material including biologically active small molecules; (3) axially positioning the head portion over the body portion such that the portions at least partially overlap; and (4) forming a fluid tight (air and liquid impermeable) seal along the overlapping portions.

The material comprising the capsule portions is not particularly limited. Preferably, the capsule portions comprise material possessing a low oxygen transmission rate. For example, it is preferred the capsule portions comprise a material having an oxygen transmission rate (as measured by ASTM D3985) of less than about 165 cm³/m²/day for 100 μm, more preferably less than about 4 cm³/m²/day for 100 μm, and most preferably less than about 1 cm³/m²/day for 100 μm. Exemplary materials comprising the capsule portions include, but are not limited to, an ingestible material such as gelatin, hydroxypropyl methylcellulose, or starch. By way of specific example, the material may include gelatin having an oxygen transmission rate of about 3.5 cm³/m²/day for 100 μm. The resulting capsules may include hard gelatin capsules or soft gelatin capsules having an oxygen transmission rate of up to about 0.04 cm³/capsule/day (ASTM D3985 at 27° C. and rel. humidity of 50%). In addition, opaque capsules are highly preferred. This can be achieved by adding pigment such as titanium dioxide to the capsule material formulation. Titanium dioxide is inert and possesses a high molecular weight, which prevents it from being absorbed into blood circulation when ingested. Opaque capsules function to prevent the degradation of the resveratrol-containing composition by light degenerative processes such as photooxidation. A commercially available, opaque capsule having low oxygen permeability is available from Capsugel (Greenwood, S.C.—www.capsugel.com), sold under the trade name Licaps®.

The system used to encapsulate the composition including biologically active small molecules material must create a fluid-tight (air and liquid impermeable) seal around capsule portions. A particularly preferred encapsulation system and process is disclosed in WO 01/08631A1, incorporated herein by reference in its entirety. In this system and associated process, a capsule head portion and a capsule body portion are placed in a filling chamber. The capsule body portion is filled with the desired dosage material, and the capsule portions are then telescopically joined such that the head portion partially overlaps the body portion. A sealing liquid including a solvent is applied in the gap formed between the overlapping sections, and the capsule is dried to remove the solvent and form a fluid-tight seal.

It is important that the encapsulation process occurs in a substantially oxygen-free environment. In addition, it is preferred the encapsulation process take place in a darkened (substantially light free) environment. As explained above, small molecules such as resveratrol lose their biological activity upon exposure to light and/or oxygen (due, e.g., to oxidation processes). Consequently, the composition containing small molecules should be mixed and/or encapsulated in a system including airtight and darkened mixing and filling chambers having a substantially oxygen-free environment. This can be achieved by using an enclosed system from which oxygen is removed. Oxygen may be removed using a vacuum, replacing the oxygen within the system with an inert gas flush, or a combination thereof. For example, the system can be purged of oxygen using a controlled nitrogen blanket. In addition, the system is kept substantially oxygen free through the use of a nitrogen flush during the encapsulation process. A nitrogen purge may also be used to remove oxygen from each individual capsule. Specifically, prior to sealing, a positive pressure can be applied to each capsule to replace any oxygen present within the capsule with nitrogen. Upon sealing, a nitrogen bubble remains within the capsule. A commercially available encapsulation system capable of filling capsules in a substantially oxygen-free and light-free environment is available from Capsugel (Greenwood, S.C.—www.capsugel.com), sold under the trade name CPS 1000 Capsule Filling Machine.

In a preferred embodiment, the compositions of the present embodiments are formulated as air-tight capsules in which encapsulation is conducted so as to prevent or minimize exposure to oxygen. In one embodiment, such encapsulation is conducted in an oxygen-free environment. For example, the components of the compositions of the present embodiments may be inserted into a capsule in an inert gas (e.g., nitrogen, argon, etc.) environment. Preferably, a nitrogen bubble (e.g., 5-20% of the capsule volume) may be introduced into the capsule to further stabilize and protect the components against oxidation (see, PCT Publication No. WO 01/08631, herein incorporated by reference). That international application has a corresponding U.S. patent application. Suitable capsules useful in the encapsulation of resveratrol and other oxidation prone ingredients of dietary supplements include Licaps® (Capsugel), an air-tight gelatin capsule. The presence of phytic acid, which has the ability to protect the components from metal-induced oxidation, augments such anti-oxidation precautions. A particularly preferred example of such a resveratrol-containing composition is Longevinex® (Resveratrol Partners, LLC, San Dimas, Calif.), which comprises resveratrol and phytic acid. Longevinex® contains as active ingredients (per capsule): 5 mg Vitamin E (as mixed tocopherols), 215 mg total resveratrol (obtained from French red wine and giant knotwood (Polygonum cuspidatum), and providing 100 mg of trans-resveratrol), 25 mg quercetin dihydrate, 75 mg phytic acid (rice bran extract), 380 mg rice bran oil, 55 mg sunflower lecithin.

Once a composition has been sealed into an air-tight capsule, it is important to maintain a low or no-oxygen environment in the packaging surrounding the capsules in order to protect the composition from oxidation should a break or leak occur in the sealed capsule. Therefore, an oxygen absorbing packette is preferably employed to reduce the presence of free oxygen. Vacuum or nitrogen-flushed packaging (bottles, pill cases, etc.) in air-tight materials is desirable.

In an alternative embodiment, the components and compositions of the present embodiments may be prepared as a microencapsulated process (see, generally, Rubiana, M. et al. (2004) Current Drug Targets, 5(5):449-455). Micro-encapsulation is a process by which tiny particles or droplets (ranging in size from a few nanometers to one micron) are coated with a protective layer to create small capsules with controlled properties. Suitable micron-sized, encapsulated, preparations can be obtained using the microencapsulation processes of Maxx Performance Inc. (Chester, N.Y.), Blue California (Rancho Santa Margarita, Calif.), Southwest Research Institute (San Antonio, Tex.), Coating Place, Inc. (Verona, Wis.), Microtek Laboratories (Dayton, Ohio), Particle Sciences, Inc. (Bethlehem, Pa.), etc. 3^(rd)-generation Longevinex® (“Longevinex-3®”) (Resveratrol Partners, LLC), which contains Vitamin D3, Vitamin E, Resveratrol, Quercetin, and Phytic Acid is a particularly preferred microencapsulated form of the compositions of the present embodiments. The present embodiments further comprises a practical method of stabilizing quercetin and other easily oxidized dietary supplement ingredients which may come in contact with oxidizing metals.

Having now generally described the embodiments, the same will be more readily understood through reference to the following examples, which are provided by way of illustration and are not intended to be limiting of the present embodiments unless specified.

Example 1 Comparative Effects of Resveratrol and Compositions of the Present Embodiments

In order to determine if the compositions of the present embodiments were more effective than resveratrol alone in mediating a resveratrol biological activity, an analysis of gene expression was conducted, comparing the modulation of gene expression achieved by calorie restriction to the modulation of gene expression achieved by the compositions of the present embodiments.

Accordingly, the ability of resveratrol alone and the resveratrol-containing compositions of the present embodiments to up-regulate survival/longevity genes or down-regulate genes whose expression enhances cellular damage was compared using the expression profile of a calorie restricted (“CR”) animal as a positive control and the expression profile of a normally fed animal as a negative control. Male B6CHF1 mice (2 months of age) were thus either placed on a 40% calorie restricted diet, provided commercially obtained trans-resveratrol (Sigma Chemical; 1.25 mg/kg per day), provided a resveratrol-containing composition of the present embodiments (Longevinex®; Resveratrol Partners LLC; 100 mg trans-resveratrol containing capsule per 80 kg human per day (i.e., 2.5 mg/kg per day of resveratrol (1.25 mg/kg per day trans-resveratrol) 0.31 mg/kg per day quercetin dihydrate, 0.94 mg/kg per day rice bran extract, 4.75 mg/kg per day rice bran oil and 0.70 mg/kg per day sunflower lecithin)). The mice were monitored until they had reached five months of age.

Body weight, serum glucose levels, serum insulin levels and lipid peroxidation in brain and muscle tissue were measured. The results showed that Longevinex® did not result in a weight increase distinguishable from control animals (FIG. 1). Serum insulin levels were found to be approximately the same as that observed in the calorie restricted animals (FIG. 2). Serum glucose levels were found to be lower than that observed in the calorie restricted animals (FIG. 3).

Example 2 Comparative Effects of Resveratrol and the Present Compositions on Gene Expression in Cardiac Tissue

The profile of expressed genes in the cardiac tissue of mice receiving resveratrol or a composition of the present embodiments (Longevinex®) was compared to that of mice placed on a calorie restricted diet and control mice. Gene expression was monitored using an Affymetrix MG430 2.0 Array, containing 45,101 probe sets per array. In cases in which the array represented the same gene with multiple probes, the probe set with the highest signal intensity was employed. Unknown genes (including uncharacterized ESTs and cDNA sequences were not analyzed. Thus, the array provided a means for analyzing 20,341 genes having a single Entrez Gene ID. Analysis was conducted substantially as described by Lee, C.-K. et al. (2002) Proc. Natl. Acad. Sci. (U.S.A.) 99:14988-14993, herein incorporated by reference. The mean of all arrays in a group were calculated. The means of treated groups were compared to the mean of the control group, and the statistical significance of any differences were determined using two-tailed t-tests (P<0.01). The results of the analysis are presented in Table 3 (submitted as a separate electronic file). In Table 3 the following abbreviations are used: CO, control; CR, calorie restricted; RES, resveratrol; LGX, Longevinex®; FC, fold change. FC is calculated as the mean of the treated group divided by the mean of the control group, and this value is then log-transformed (base 2) for statistical purposes. As an example, a gene that is expressed at 100 in the control and 200 in a treated group would be have an Fc of 2 (i.e., a twofold increase in expression); a gene that is expressed at 100 in the control and 50 in the treated group, would have an Fc of −2 (i.e., a twofold decrease in expression).

Treatment of human umbilical vein epithelial cells with ferulic acid, quercetin or resveratrol has been reported to result in changes to gene expression of greater than 2-fold down-regulation of 363 genes, and greater than 2-fold up-regulation of 233 genes of 10,000 genes probed (Nicholson, S. K. et al. (2008) Proc. Nutr. Soc. 67(1):42-47). In contrast, Table 3 shows that 2,829 genes were found to exhibit a statistically significant change in expression in treated vs. control mice. Of these genes, 7% were found to exhibit altered expression in mice that had been subjected to only calorie restriction; 8% were found to exhibit altered expression in mice subjected only to resveratrol. Combining calorie restriction with resveratrol administration failed to alter the expression of any additional genes. In contrast, administration of Longevinex® was found to alter the expression of 61% of the 2,829 genes. Administration of Longevinex® to calorie restricted mice was found to alter the expression of an additional 2% of the genes. Administration of Longevinex® to mice receiving resveratrol was found to alter the expression of an additional 21% of the genes. Thus, Longevinex® alone or in combination with other regimens was found to affect 85% (2,406) of the total genes showing altered expression.

Several genes of particular interest showed expression patterns indicating that compositions of the present embodiments (Longevinex®) up-regulated survival/longevity genes or down-regulate genes whose expression enhances cellular damage to a greater extent than resveratrol, including the sirtuin family of genes, Pgc-1α, Uncoupling protein-3, and pyruvate dehydrogenase kinase 4.

The sirtuin family of genes, and in particular Sirtuin 1, are thought to be critical mediators of extended lifespans (Boily, G. et al. (2008) PLoS ONE 3(3):e1759; Huang, J. et al. (2008) PLoS ONE 3(3):e1710). Whereas mice receiving resveratrol showed only a 1.22 fold decrease in expression and mice subjected to a calorie restricted diet showed only a 1.12 fold reduction in Sirtuin 1 expression, expression of Sirtuin 1 was found to be decreased 1.71 fold in mice receiving Longevinex®. Pgc-1α (peroxisome proliferative activated receptor, gamma, coactivator 1 alpha; ppargc1a) is a transcriptional co-factor that controls energy metabolism and mitochondrial biogenesis; its expression is increased in skeletal muscle tissue upon long-term calorie restriction (Conley, K. E. et al. (2007) Curr. Opin. Clin. Nutr. Metab. Care. 10(6):688-692; Wu, Z. et al. (2007) Expert Opin. Ther. Targets 11(10):1329-1338). Whereas mice receiving resveratrol showed only a 1.6 fold increase in expression and mice subjected to a calorie restricted diet showed no increase in Pgc-1α expression, mice receiving Longevinex® showed a 1.94 fold increase in Pgc-1α expression.

Uncoupling protein-3 is believed to be a target of Pgc-1α and to play a role in fatty acid metabolism; its expression is increased in cardiac tissue upon long-term calorie restriction (Bézaire, V. et al. (Epub 2007 January 3) FASEB J. 21(2):312-324; Chan, C. B. et al. (2006) Curr. Diabetes Rev. 2(3):271-283). Whereas mice receiving resveratrol showed only a 2.02 fold increase in expression and mice subjected to a calorie restricted diet showed only a 1.8 fold increase in uncoupling protein-3 expression, mice receiving Longevinex® showed a 2.79 fold increase in uncoupling protein-3 expression. Pyruvate dehydrogenase kinase 4 coordinates fuel selection during fasting to promote fatty acid metabolism (Sugden, M. C. et al. (2006) Arch. Physiol. Biochem. 112(3):139-149; Pilegaard, H. et al. (2004) Proc. Nutr. Soc. 63(2):221-226; Sugden, M. C. (2003) Obes. Res. 11(2):167-169). It is a target of Pgc-1α and is induced in multiple tissues by long-term calorie restriction. Whereas mice receiving resveratrol showed only a 2.78 fold increase in expression and mice subjected to a calorie restricted diet showed only a 1.48 fold increase in pyruvate dehydrogenase kinase 4 expression, mice receiving Longevinex® showed a 3.25 fold increase in pyruvate dehydrogenase kinase 4 expression.

Analysis of the genes up-regulated or down-regulated by a compound of the present embodiments (Longevinex®) revealed that oxidative phosphorylation genes, which are involved in mitochondrial ATP production, were markedly up-regulated, as noted in Table 4.

TABLE 4 FC CR FC RES FCLGX Gene 1.11 1.14 1.32 Ndufa5 −1.00 −1.20 −1.42 Ndufaf1 −1.04 −1.13 −1.22 Ndufb3 1.13 1.06 1.27 Ndufb8 1.12 1.18 1.28 Ndufb7 −1.34 −1.55 −2.65 Ndufab1 1.07 1.20 1.51 Ndufc1 −1.07 −1.30 −1.39 Ndufc2 1.08 1.11 1.37 Ndufs1 1.13 1.10 1.26 Ndufs2 1.09 1.12 1.23 Ndufs3 1.04 1.19 1.33 Ndufs5 1.13 1.18 1.44 Ndufs7 −1.02 1.03 −1.23 Ndufs8 1.14 1.18 1.21 Ndufv1 1.11 1.13 1.34 Ndufv2 1.17 1.13 1.43 Sdha 1.16 1.02 1.23 Sdhd 1.46 1.29 1.49 Sulf2 1.01 −1.25 −1.33 Uqcc 1.10 1.19 1.34 Uqcrc1 1.05 1.07 1.38 Uqcrfs1 1.20 1.50 1.94 Cox4i2 1.13 1.05 1.39 Cox5a 1.23 1.13 1.61 Cox8a

Example 3 Biochemical Pathways Affected by the Compositions of the Present Embodiments

Recent research has suggested that complex traits are emergent properties of molecular networks that are modulated by complex genetic loci and environmental factors. Chen, Y. et al. (Epub 2008 March 16) Nature 452(7186):429-435). Indeed, research within the last decade has revealed that most chronic illnesses such as cancer, cardiovascular and pulmonary diseases, neurological diseases, diabetes, and autoimmune diseases exhibit dysregulation of multiple cell signaling pathways (Harikumar, K. B. et al. (Epub Feb. 15, 2008) Cell Cycle. 2008:7(8)). The compounds of the present embodiments were therefore evaluated for their effect on the expression of biochemical pathways and were found to affect the expression of genes involved in 220 biological processes (P<0.05), as shown in Table 5.

TABLE 5 Changed Genes by LT- in GO ID Biological Processes Treatment CR Series CR RES LGX GO: 0051128 Regulation Of Cellular Component CR only 0.0277 51 5 Organization And Biogenesis GO: 0001558 Regulation Of Cell Growth CR only 74 5 GO: 0006820 Anion Transport CR only 155 6 GO: 0008361 Regulation Of Cell Size CR only 102 6 GO: 0016049 Cell Growth CR only 90 5 GO: 0030217 T Cell Differentiation CR only 55 3 GO: 0030595 Leukocyte Chemotaxis CR only 18 2 GO: 0045580 Regulation Of T Cell CR only 15 2 Differentiation GO: 0045792 Negative Regulation Of Cell Size CR only 16 2 GO: 0048705 Skeletal Morphogenesis CR only 20 2 GO: 0051246 Regulation Of Protein Metabolic CR only 204 8 Process GO: 0033554 Cellular Response To Stress RES only 0.0074 14 3 GO: 0006888 ER To Golgi Vesicle-Mediated RES only 0.0284 16 3 Transport GO: 0000723 Telomere Maintenance RES only 17 3 GO: 0001958 Endochondral Ossification RES only 8 2 GO: 0006281 DNA Repair RES only 178 13 GO: 0006353 Transcription Termination RES only 6 2 GO: 0006446 Regulation Of Translational RES only 20 4 Initiation GO: 0006596 Polyamine Biosynthetic Process RES only 5 2 GO: 0006625 Protein Targeting To Peroxisome RES only 5 2 GO: 0006825 Copper Ion Transport RES only 9 3 GO: 0006919 Caspase Activation RES only 16 3 GO: 0006974 Response To DNA Damage RES only 217 15 Stimulus GO: 0006983 ER Overload Response RES only 5 2 GO: 0007017 Microtubule-Based Process RES only 155 12 GO: 0007091 Mitotic Metaphase/Anaphase RES only 8 2 Transition GO: 0007143 Female Meiosis RES only 8 2 GO: 0008299 Isoprenoid Biosynthetic Process RES only 19 3 GO: 0045351 Interferon Type I Biosynthetic RES only 6 2 Process GO: 0045577 Regulation Of B Cell RES only 8 2 Differentiation GO: 0046330 Positive Regulation Of JNK RES only 8 2 Cascade GO: 0048193 Golgi Vesicle Transport RES only 37 6 GO: 0050673 Epithelial Cell Proliferation RES only 30 4 GO: 0006119 Oxidative Phosphorylation LGX only 0.0001 39 10 GO: 0042773 ATP Synthesis Coupled Electron LGX only 0.0019 11 5 Transport GO: 0030036 Actin Cytoskeleton Organization LGX only 0.0024 146 34 And Biogenesis GO: 0006629 Lipid Metabolic Process LGX only 0.0146 535 89 GO: 0044255 Cellular Lipid Metabolic Process LGX only 0.0147 459 80 GO: 0001701 In Utero Embryonic Development LGX only 0.0195 101 19 GO: 0040008 Regulation Of Growth LGX only 0.0242 135 23 GO: 0000375 RNA Splicing, Via LGX only 0.0251 39 10 Transesterification Reactions GO: 0000398 Nuclear Mrna Splicing, Via LGX only 0.0251 39 10 Spliceosome GO: 0006366 Transcription From RNA LGX only 0.0264 392 72 Polymerase II Promoter GO: 0006357 Regulation Of Transcription From LGX only 0.0276 351 59 RNA Polymerase II Promoter GO: 0016044 Membrane Organization And LGX only 0.0292 209 34 Biogenesis GO: 0006066 Alcohol Metabolic Process LGX only 0.0299 222 41 GO: 0065002 Intracellular Protein Transport LGX only 0.0372 59 16 Across A Membrane GO: 0006099 Tricarboxylic Acid Cycle LGX only 0.0396 23 7 GO: 0009060 Aerobic Respiration LGX only 0.0396 24 7 GO: 0044265 Cellular Macromolecule Catabolic LGX only 0.0417 201 41 Process GO: 0006006 Glucose Metabolic Process LGX only 0.0441 83 16 GO: 0045333 Cellular Respiration LGX only 0.0484 28 8 GO: 0000038 Very-Long-Chain Fatty Acid LGX only 5 3 Metabolic Process GO: 0000059 Protein Import Into Nucleus, LGX only 15 7 Docking GO: 0000186 Activation Of MAPKK Activity LGX only 10 5 GO: 0001525 Angiogenesis LGX only 124 26 GO: 0001568 Blood Vessel Development LGX only 188 42 GO: 0001570 Vasculogenesis LGX only 27 8 GO: 0001839 Neural Plate Morphogenesis LGX only 40 9 GO: 0001841 Neural Tube Formation LGX only 39 9 GO: 0001843 Neural Tube Closure LGX only 29 7 GO: 0001935 Endothelial Cell Proliferation LGX only 8 4 GO: 0002026 Cardiac Inotropy LGX only 10 4 GO: 0003007 Heart Morphogenesis LGX only 32 8 GO: 0005978 Glycogen Biosynthetic Process LGX only 11 5 GO: 0006007 Glucose Catabolic Process LGX only 44 11 GO: 0006098 Pentose-Phosphate Shunt LGX only 7 3 GO: 0006118 Electron Transport LGX only 303 65 GO: 0006120 Mitochondrial Electron Transport, LGX only 6 5 NADH To Ubiquinone GO: 0006171 Camp Biosynthetic Process LGX only 14 5 GO: 0006259 DNA Metabolic Process LGX only 524 77 GO: 0006323 DNA Packaging LGX only 209 37 GO: 0006325 Establishment And/Or Maintenance LGX only 203 34 Of Chromatin Architecture GO: 0006333 Chromatin Assembly Or LGX only 80 15 Disassembly GO: 0006352 Transcription Initiation LGX only 27 7 GO: 0006354 RNA Elongation LGX only 5 3 GO: 0006367 Transcription Initiation From RNA LGX only 11 5 Polymerase II Promoter GO: 0006396 RNA Processing LGX only 319 63 GO: 0006397 Mrna Processing LGX only 213 43 GO: 0006414 Translational Elongation LGX only 19 6 GO: 0006461 Protein Complex Assembly LGX only 122 28 GO: 0006468 Protein Amino Acid LGX only 545 83 Phosphorylation GO: 0006470 Protein Amino Acid LGX only 99 18 Dephosphorylation GO: 0006473 Protein Amino Acid Acetylation LGX only 12 4 GO: 0006508 Proteolysis LGX only 545 85 GO: 0006520 Amino Acid Metabolic Process LGX only 198 34 GO: 0006606 Protein Import Into Nucleus LGX only 53 13 GO: 0006612 Protein Targeting To Membrane LGX only 15 5 GO: 0006631 Fatty Acid Metabolic Process LGX only 142 35 GO: 0006635 Fatty Acid Beta-Oxidation LGX only 13 6 GO: 0006638 Neutral Lipid Metabolic Process LGX only 21 6 GO: 0006641 Triacylglycerol Metabolic Process LGX only 17 6 GO: 0006662 Glycerol Ether Metabolic Process LGX only 23 6 GO: 0006766 Vitamin Metabolic Process LGX only 57 14 GO: 0006807 Nitrogen Compound Metabolic LGX only 315 49 Process GO: 0006869 Lipid Transport LGX only 67 16 GO: 0006913 Nucleocytoplasmic Transport LGX only 89 23 GO: 0006914 Autophagy LGX only 21 8 GO: 0007031 Peroxisome Organization And LGX only 22 7 Biogenesis GO: 0007182 Common-Partner SMAD Protein LGX only 8 4 Phosphorylation GO: 0007190 Adenylate Cyclase Activation LGX only 12 4 GO: 0007242 Intracellular Signaling Cascade LGX only 915 133 GO: 0007369 Gastrulation LGX only 55 13 GO: 0007498 Mesoderm Development LGX only 44 13 GO: 0007507 Heart Development LGX only 158 39 GO: 0007512 Adult Heart Development LGX only 9 4 GO: 0007517 Muscle Development LGX only 105 19 GO: 0008016 Regulation Of Heart Contraction LGX only 27 9 GO: 0008286 Insulin Receptor Signaling LGX only 24 7 Pathway GO: 0009308 Amine Metabolic Process LGX only 294 46 GO: 0009653 Anatomical Structure LGX only 993 143 Morphogenesis GO: 0009790 Embryonic Development LGX only 387 61 GO: 0009792 Embryonic Development Ending In LGX only 190 32 Birth Or Egg Hatching GO: 0010003 Gastrulation (Sensu Mammalia) LGX only 17 6 GO: 0015804 Neutral Amino Acid Transport LGX only 6 3 GO: 0015908 Fatty Acid Transport LGX only 6 3 GO: 0016071 Mrna Metabolic Process LGX only 240 45 GO: 0016192 Vesicle-Mediated Transport LGX only 365 61 GO: 0016310 Phosphorylation LGX only 601 95 GO: 0016311 Dephosphorylation LGX only 111 20 GO: 0016481 Negative Regulation Of LGX only 223 40 Transcription GO: 0016485 Protein Processing LGX only 58 14 GO: 0016540 Protein Autoprocessing LGX only 30 9 GO: 0016567 Protein Ubiquitination LGX only 36 9 GO: 0016568 Chromatin Modification LGX only 152 27 GO: 0016574 Histone Ubiquitination LGX only 5 3 GO: 0019395 Fatty Acid Oxidation LGX only 20 8 GO: 0019752 Carboxylic Acid Metabolic Process LGX only 403 78 GO: 0030163 Protein Catabolic Process LGX only 162 31 GO: 0030239 Myofibril Assembly LGX only 12 5 GO: 0030323 Respiratory Tube Development LGX only 58 12 GO: 0030324 Lung Development LGX only 57 12 GO: 0030855 Epithelial Cell Differentiation LGX only 34 8 GO: 0030856 Regulation Of Epithelial Cell LGX only 7 3 Differentiation GO: 0030865 Cortical Cytoskeleton Organization LGX only 10 5 And Biogenesis GO: 0031032 Actomyosin Structure Organization LGX only 16 5 And Biogenesis GO: 0032147 Activation Of Protein Kinase LGX only 28 8 Activity GO: 0035051 Cardiac Cell Differentiation LGX only 13 6 GO: 0035239 Tube Morphogenesis LGX only 128 25 GO: 0035295 Tube Development LGX only 174 36 GO: 0042254 Ribosome Biogenesis And LGX only 97 18 Assembly GO: 0042692 Muscle Cell Differentiation LGX only 58 14 GO: 0043009 Chordate Embryonic Development LGX only 187 32 GO: 0043087 Regulation Of Gtpase Activity LGX only 59 12 GO: 0043623 Cellular Protein Complex LGX only 39 11 Assembly GO: 0043631 RNA Polyadenylation LGX only 11 4 GO: 0044257 Cellular Protein Catabolic Process LGX only 116 27 GO: 0045214 Sarcomere Organization LGX only 9 4 GO: 0045761 Regulation Of Adenylate Cyclase LGX only 16 5 Activity GO: 0045893 Positive Regulation Of LGX only 225 44 Transcription, DNA-Dependent GO: 0045944 Positive Regulation Of LGX only 186 34 Transcription From RNA Polymerase II Promoter GO: 0046058 Camp Metabolic Process LGX only 17 5 GO: 0046777 Protein Amino Acid LGX only 29 9 Autophosphorylation GO: 0048276 Gastrulation (Sensu Vertebrata) LGX only 24 7 GO: 0048514 Blood Vessel Morphogenesis LGX only 160 36 GO: 0048646 Anatomical Structure Formation LGX only 171 34 GO: 0050658 RNA Transport LGX only 48 11 GO: 0051028 Mrna Transport LGX only 45 11 GO: 0051146 Striated Muscle Cell LGX only 26 11 Differentiation GO: 0051170 Nuclear Import LGX only 54 13 GO: 0055001 Muscle Cell Development LGX only 13 5 GO: 0055002 Striated Muscle Cell Development LGX only 12 5 GO: 0055007 Cardiac Muscle Cell LGX only 9 6 Differentiation GO: 0055012 Ventricular Cardiac Muscle Cell LGX only 6 4 Differentiation GO: 0051016 Barbed-End Actin Filament CR & RES 0.0487 17 2 3 Capping GO: 0030029 Actin Filament-Based Process CR & LGX 0.0049 157 6 37 GO: 0006084 Acetyl-Coa Metabolic Process CR & LGX 0.0068 33 3 11 GO: 0045941 Positive Regulation Of CR & LGX 0.0119 267 8 48 Transcription GO: 0006915 Apoptosis CR & LGX 0.0172 537 14 84 GO: 0012501 Programmed Cell Death CR & LGX 0.0198 544 14 84 GO: 0046356 Acetyl-Coa Catabolic Process CR & LGX 0.0396 24 2 8 GO: 0008219 Cell Death CR & LGX 0.0410 564 14 84 GO: 0006364 Rrna Processing CR & LGX 50 3 11 GO: 0006519 Amino Acid And Derivative CR & LGX 253 8 41 Metabolic Process GO: 0006796 Phosphate Metabolic Process CR & LGX 714 17 114 GO: 0006839 Mitochondrial Transport CR & LGX 20 2 9 GO: 0007005 Mitochondrion Organization And CR & LGX 58 4 19 Biogenesis GO: 0007167 Enzyme Linked Receptor Protein CR & LGX 252 9 46 Signaling Pathway GO: 0007179 Transforming Growth Factor Beta CR & LGX 42 3 11 Receptor Signaling Pathway GO: 0009056 Catabolic Process CR & LGX 474 13 79 GO: 0016265 Death CR & LGX 564 14 84 GO: 0030833 Regulation Of Actin Filament CR & LGX 10 2 4 Polymerization GO: 0008104 Protein Localization RES & 0.0007 663 38 127 LGX GO: 0015031 Protein Transport RES & 0.0011 581 38 121 LGX GO: 0045184 Establishment Of Protein RES & 0.0028 610 38 123 Localization LGX GO: 0006886 Intracellular Protein Transport RES & 0.0098 357 26 75 LGX GO: 0006605 Protein Targeting RES & 0.0099 161 12 34 LGX GO: 0044249 Cellular Biosynthetic Process RES & 0.0107 710 45 117 LGX GO: 0009058 Biosynthetic Process RES & 0.0120 979 60 155 LGX GO: 0006412 Translation RES & 0.0364 338 25 62 LGX GO: 0044262 Cellular Carbohydrate Metabolic RES & 0.0471 221 18 49 Process LGX GO: 0005975 Carbohydrate Metabolic Process RES & 316 21 60 LGX GO: 0005976 Polysaccharide Metabolic Process RES & 42 9 15 LGX GO: 0005977 Glycogen Metabolic Process RES & 31 7 13 LGX GO: 0006091 Generation Of Precursor RES & 390 24 88 Metabolites And Energy LGX GO: 0006112 Energy Reserve Metabolic Process RES & 35 7 13 LGX GO: 0006413 Translational Initiation RES & 40 6 9 LGX GO: 0006511 Ubiquitin-Dependent Protein RES & 109 9 27 Catabolic Process LGX GO: 0006512 Ubiquitin Cycle RES & 356 27 79 LGX GO: 0007178 Transmembrane Receptor Protein RES & 75 7 19 Serine/Threonine Kinase Signaling LGX Pathway GO: 0007264 Small Gtpase Mediated Signal RES & 320 22 62 Transduction LGX GO: 0008380 RNA Splicing RES & 162 12 30 LGX GO: 0009059 Macromolecule Biosynthetic RES & 525 35 90 Process LGX GO: 0019941 Modification-Dependent Protein RES & 111 9 27 Catabolic Process LGX GO: 0043085 Positive Regulation Of Enzyme RES & 40 5 11 Activity LGX GO: 0043280 Positive Regulation Of Caspase RES & 17 3 5 Activity LGX GO: 0043281 Regulation Of Caspase Activity RES & 27 5 8 LGX GO: 0045454 Cell Redox Homeostasis RES & 40 6 9 LGX GO: 0050790 Regulation Of Catalytic Activity RES & 241 21 53 LGX GO: 0008064 Regulation Of Actin All 0.0139 30 5 4 9 Polymerization And/Or Depolymerization GO: 0030832 Regulation Of Actin Filament All 0.0139 31 5 4 9 Length GO: 0046907 Intracellular Transport All 0.0287 523 16 43 113 GO: 0008154 Actin Polymerization And/Or All 0.0414 39 5 6 12 Depolymerization GO: 0051649 Establishment Of Cellular All 0.0467 653 17 45 125 Localization GO: 0006457 Protein Folding All 124 6 13 34 GO: 0006996 Organelle Organization And All 897 27 53 158 Biogenesis GO: 0007010 Cytoskeleton Organization And All 403 12 26 70 Biogenesis GO: 0007018 Microtubule-Based Movement All 72 4 9 14 GO: 0030041 Actin Filament Polymerization All 17 2 3 7 GO: 0051258 Protein Polymerization All 32 6 6 8

Calorie restriction affected genes associated with 5% of these processes, administration of resveratrol affected genes associated with 10% of these processes. Compounds of the present embodiments (e.g., Longevinex®) were found to affect 85% of these processes. Administration of resveratrol to calorie restricted mice failed to affect any genes in any of these processes. Administration of Longevinex® to calorie restricted mice was found to affect genes associated with 8% of these processes. Administration of both resveratrol and Longevinex® was found to affect genes associated with 12% of these processes. Table 6 shows the modulation of the genes of the oxidative phosphorylation pathway (GO:0006119) caused by calorie restriction (CR), resveratrol alone (Res), or Longevinex® (LGX).

TABLE 6 Modulation Of The Genes Of The Oxidative Phosphorylation Pathway (GO: 0006119) Fold Change Gene CR Res LGX 1110020P15Rik 1.06 1.09 1.26 Atp5a1 1.09 1.02 1.29 Atp5b 1.10 1.01 1.27 Atp5c1 −1.16 −1.28 −1.16 Atp5f1 1.09 1.08 1.19 Atp5g1 1.26 −1.58 −1.17 Atp5g3 1.06 −1.11 −1.01 Atp5h 1.07 1.04 1.37 Atp5j 1.07 −1.00 1.24 Atp5k 1.05 1.02 1.24 Atp6v0d1 1.03 −1.21 −1.19 Atp6v0d2 1.04 1.65 1.21 Atp6v1a −1.04 −1.18 −1.35 Atp6v1b2 1.27 −1.16 −1.23 Atp6v1c1 −1.10 −1.07 −1.06 Atp6v1c2 2.17 1.42 −1.00 Atp6v1d 1.13 −1.09 −1.05 Atp6v1e1 1.05 −1.42 −1.42 Atp6v1e2 1.11 1.28 1.30 Atp6v1f −1.14 −1.21 −1.44 Atp6v1h −1.17 −1.19 −1.11 Atp7a −1.13 −1.18 −1.29 Cyc1 1.14 1.08 1.29 Msh2 1.05 −1.03 −1.15 Ndufa7 −1.07 −1.14 −1.07 Ndufb9 1.07 1.07 1.25 Ndufc2 −1.07 −1.30 −1.39 Ndufs1 1.08 1.11 1.37 Ndufs3 1.09 1.12 1.23 Ndufs7 1.13 1.18 1.44 Ndufv1 1.14 1.18 1.21 Uqcr 1.03 1.10 1.30 Uqcrb −1.09 −1.00 −1.22 Uqcrh 1.05 −1.40 −1.34

Table 7 shows the modulation of the genes of the glucose metabolism pathway (GO:0006006) caused by calorie restriction (CR), resveratrol alone (Res), or the compositions of the present embodiments (LGX).

TABLE 7 Modulation Of The Genes Of The Glucose Metabolism Pathway (GO: 0006006) Fold Change Gene CR Res LGX 6430537H07 −1.26 −1.73 −1.04 Rik Acn9 −1.04 −1.08 −1.22 Adipoq 1.74 1.24 2.14 Adpgk −1.02 1.24 1.37 Akt1 1.11 1.66 1.73 Aldoart1 2.17 2.37 3.08 Aldoart2 −1.05 1.16 1.05 Aldob −1.06 1.24 1.21 Aldoc −1.32 1.14 1.32 Atf3 −1.86 −1.47 −1.68 Atf4 −1.06 1.07 1.10 Bad 1.05 1.10 −1.07 Bpgm −1.28 1.35 1.57 Cacna1a −1.31 1.03 −1.21 Car5a −2.59 1.19 −1.14 Dcxr 1.05 1.08 1.14 Dhtkd1 −1.45 −1.32 −1.08 Dlat 1.05 −1.09 −1.07 Eno2 −1.19 1.32 1.86 Eno3 1.17 1.26 1.37 Fabp5 1.14 −1.13 −1.26 Fbp1 −1.50 −1.25 1.20 Fbp2 −1.16 1.42 1.47 G6pc 1.42 −1.62 −1.71 G6pd2 1.93 1.37 2.90 G6pdx 1.30 1.00 1.38 Ganc −1.26 1.08 −1.30 Gapdh 1.15 1.09 1.35 Gapdhs 1.35 1.62 1.50 Gck 1.16 1.26 1.16 Gpd1 1.83 1.51 2.41 Gpd2 1.48 −1.41 1.17 H6pd 1.33 1.43 2.06 Hibadh 1.09 1.17 1.15 Hk1 1.12 −1.24 −1.34 Hk3 2.23 1.60 1.77 Hkdc1 2.64 2.10 1.68 Ins1 1.19 1.49 1.37 Ldha 1.10 −1.03 1.04 Ldha16b 1.15 1.45 2.73 Ldhb 1.21 1.35 1.60 Ldhc 1.94 2.25 2.44 Lep −1.57 −1.96 −1.43 Lrrc16 1.00 −1.10 1.03 Mapk14 −1.10 −1.13 −1.51 Mdh1 1.07 1.08 1.41 Mdh2 1.10 1.01 1.15 Npy1r 1.11 1.37 1.53 Nr3c1 1.14 −1.14 1.10 Ogdh 1.32 1.23 1.38 Onecut1 −1.32 −2.13 −2.05 Pck1 1.68 2.36 4.03 Pck2 1.06 −1.09 −1.05 Pcx 1.40 1.33 1.60 Pdha1 1.12 1.09 1.30 Pdha2 1.78 −1.03 1.57 Pdk1 −1.01 1.01 −1.18 Pdk2 1.11 1.11 1.24 Pdk3 −2.02 −1.04 1.21 Pdk4 1.48 2.78 3.25 Pdx1 −3.03 −1.37 −1.14 Pfk1 1.19 −1.15 −1.11 Pfkm 1.13 1.07 1.02 Pfkp 1.32 1.13 1.24 Pgam1 1.15 1.01 1.07 Pgam2 1.27 1.38 1.81 Pgd 1.20 −1.05 1.16 Pgk2 −1.79 1.29 −1.01 Pgls 1.28 1.24 1.42 Pgm1 1.05 1.14 1.21 Pgm2 1.11 1.09 1.03 Pgm211 1.19 1.31 1.11 Pgm3 1.13 −1.09 −1.29 Pik3ca −1.05 1.34 1.21 Pklr 1.12 −1.08 −1.47 Pkm2 1.31 1.34 1.70 Ppara 1.14 −1.06 −1.28 Prkaa1 −1.08 1.17 −1.38 Rpia 1.04 1.06 1.12 Sds −1.65 −1.16 2.01 S1c2a8 1.11 1.30 1.19 Taldo1 1.12 1.04 1.08 Tnf −1.16 −1.73 1.11 Tpi1 1.15 1.06 1.24 Uevld −1.01 −1.12 −1.28

Table 8 shows the modulation of the genes of the tricarboxylic acid metabolism pathway (GO:0006099) caused by calorie restriction (CR), resveratrol alone (Res), or the compositions of the present embodiments (LGX).

TABLE 8 Modulation Of The Genes Of The Tricarboxylic Acid Metabolism Pathway (GO: 0006099) Fold Change Gene CR Res LGX 2610507B11 1.10 1.06 1.25 Rik Aco1 1.00 −1.01 −1.05 Aco2 1.16 1.13 1.39 Atp5g3 1.06 −1.11 −1.01 Cs 1.22 1.07 1.46 Dlst 1.21 1.08 1.24 Fh1 −1.01 1.05 1.18 Idh2 1.12 1.21 1.36 Idh3a 1.16 −1.02 1.01 Idh3b 1.22 1.30 2.06 Idh3g 1.02 −1.06 −1.02 Mdh1 1.07 1.08 1.41 Mdh1b −1.23 −1.20 −1.00 Mdh2 1.10 1.01 1.15 Polr3h −1.19 −1.20 −1.34 Sdha 1.17 1.13 1.43 Sdhb 1.08 1.13 1.42 Sdhc −1.01 −1.06 −1.20 Sdhd 1.16 1.02 1.23 Sucla2 1.01 −1.01 1.05 Suclg1 1.08 −1.07 1.00 Suclg2 −1.03 −1.00 −1.25

Table 9 shows the modulation of the genes of the fatty acid metabolism pathway (GO:0006631) caused by calorie restriction (CR), resveratrol alone (Res), or the compositions of the present embodiments (LGX).

TABLE 9 Modulation Of The Genes Of The Fatty Acid Metabolism Pathway (GO: 0006631) Fold Change Gene CR Res LGX 2010111I01 1.07 −1.17 −1.29 Rik Aacs 1.35 −1.12 1.32 Aasdh −1.06 −1.69 −2.00 Abat −1.16 1.03 1.56 Acaa2 1.07 1.27 1.41 Acad1 1.19 1.21 1.85 Acadm −1.02 −1.10 −1.02 Acads 1.08 1.20 1.40 Acadvl 1.06 1.14 1.38 Acotl1 1.22 −1.08 1.18 Acotl2 −1.09 −1.16 1.59 Acot2 −1.35 2.13 1.58 Acot4 1.58 1.65 2.24 Acot5 2.89 6.34 2.39 Acot7 1.20 1.03 1.06 Acot8 1.05 −1.05 1.08 Acox1 −1.06 1.06 −1.03 Acox2 1.17 1.01 2.52 Acox3 1.48 1.70 1.84 Acoxl −1.85 −1.39 −1.08 Acsbg1 1.64 2.24 1.62 Acsbg2 −1.55 −1.14 −1.37 Acsf3 1.28 1.17 1.57 Acsl1 1.05 1.21 1.38 Acsl3 −1.91 −2.10 −1.17 Acsl4 −1.34 −1.20 −1.35 Acsl5 1.19 1.04 1.19 Acsl6 −1.15 −1.23 −1.26 Acsm1 1.27 1.25 1.43 Acsm2 −1.33 1.06 −1.19 Acsm3 −1.03 1.12 2.21 Acsm5 −1.38 1.14 1.08 Adipoq 1.74 1.24 2.14 Adipor1 1.08 1.03 −1.10 Adipor2 −1.16 1.11 1.15 Agpat6 1.15 1.15 1.32 Agt 1.42 1.57 2.50 Aldh5a1 1.25 1.15 1.17 Alox12 1.04 1.08 1.02 Alox12e −2.02 −2.10 1.18 Alox15 1.12 1.10 1.43 Alox5 1.18 1.22 1.32 Alox5ap 1.07 −1.08 −1.09 Alox8 1.27 1.12 2.31 Aloxe3 −1.14 1.00 1.21 Ankrd23 1.06 1.23 −1.09 Apoa2 1.24 1.29 1.34 Baat 2.33 2.78 2.42 Brca1 −1.08 1.29 1.36 C1qtnf2 −1.23 −1.02 −1.05 Cav1 1.14 1.18 1.45 Ces3 −1.16 1.06 1.23 Cpt1a −1.04 1.27 1.49 Cpt1b 1.07 1.27 1.45 Cpt1c −1.69 1.29 −1.22 Cpt2 −1.14 1.01 −1.03 Crat 1.16 1.45 1.71 Crot −1.11 −1.07 −1.37 Cryl1 −1.44 −1.14 −1.31 Cyb5 −1.10 −1.21 −1.10 Dci 1.06 1.13 1.24 Degs1 1.02 −1.16 −1.00 Ech1 1.00 1.06 1.30 Echdc2 1.06 1.19 1.32 Echs1 1.07 1.01 −1.09 Ehhadh −1.02 1.12 1.00 Elovl1 −1.03 1.15 1.18 Elovl2 −1.91 −1.31 −1.34 Elovl3 −1.12 1.11 1.47 Elovl4 1.00 1.45 −1.29 Elovl5 −1.12 −1.68 −1.91 Elov16 2.36 1.27 2.38 Elov17 1.41 1.20 1.39 Fa2h −1.27 1.18 1.04 Fads1 1.19 1.27 1.28 Fads2 1.10 1.15 1.39 Fads3 1.13 1.38 1.35 Fasn 2.54 1.54 3.10 Fcer1a 1.55 1.73 1.05 Ggtla1 −1.03 1.15 1.20 Gpam −1.09 1.34 1.39 Hadh 1.08 1.18 1.36 Hadha 1.15 1.27 1.43 Hadhb 1.80 1.57 1.51 Hao3 −1.71 −4.04 1.13 Hnf1a 1.20 1.81 1.06 Hpgd 1.17 −1.14 −2.59 Hsd17b4 1.15 1.25 1.44 Lcn5 1.58 1.74 2.30 Lta4h 1.38 1.68 1.49 Ltc4s 1.46 −1.05 1.19 Lypla1 −1.05 −1.32 −1.93 Lypla2 −1.00 −1.31 −1.13 Lypla3 1.31 1.42 1.41 Mapk14 −1.10 −1.13 −1.51 Mcat 1.04 1.01 −1.15 Mecr −1.04 1.09 1.21 Mlstd1 −1.18 1.29 1.78 Mlstd2 −1.20 −1.19 −1.29 Mlycd −1.01 1.55 1.43 Myo5a 1.21 1.09 1.09 Ncf1 −1.16 1.07 −1.25 Ndufab1 −1.34 −1.55 −2.65 Olah 1.33 −1.02 1.11 Oxsm −1.02 1.04 −1.29 Pccb 1.01 −1.01 −1.02 Pdpn −1.14 −1.04 1.22 Pecr −1.01 −1.03 1.00 Pex13 −1.05 −1.03 −1.04 Pex5 1.43 1.70 2.17 Pex7 −1.16 −1.36 −1.44 Phyh 1.10 1.15 1.20 Plp1 −1.03 1.06 −1.29 Ppara 1.14 −1.06 −1.28 Ppard 1.20 1.09 1.59 Prkaa1 −1.08 1.17 −1.38 Prkaa2 −1.17 −1.22 −1.31 Prkab1 −1.12 1.04 1.02 Prkab2 1.04 −1.07 −1.38 Prkag1 1.09 −1.14 −1.02 Prkag2 −1.05 −1.16 1.03 Prkag3 −1.24 1.34 −1.45 Prkar2b 1.95 2.01 2.24 Ptgds −1.29 1.05 −1.10 Ptgds2 −1.77 −1.02 −1.12 Ptges −1.05 −1.30 −1.38 Ptges2 1.20 1.04 −1.03 Ptges3 −1.08 −1.03 −1.07 Ptgis 1.16 1.17 1.66 Ptgs1 1.18 1.26 1.37 Ptgs2 1.01 1.25 1.35 Qk −1.06 −1.52 −2.08 Rnpep 1.13 −1.07 −1.36 Scap 1.34 1.37 1.70 Scd1 2.18 1.67 3.27 Scd2 1.19 −1.03 1.33 Scd3 −1.37 1.36 −1.01 Scp2 −1.02 1.06 1.16 Slc27a1 1.06 2.03 2.42 Slc27a2 −1.52 −1.96 1.41 Slc27a3 1.31 1.84 1.65 Slc27a4 1.23 1.25 1.20 Slc27a5 −1.57 −1.03 −1.05 Syk 1.73 1.76 2.09 Tbxas1 1.00 −1.06 −1.03 Tnfrsf1a −1.01 1.53 1.47 Tnxb 1.59 1.54 2.01 Tpi1 1.15 1.06 1.24 Tyrp1 −1.43 −1.18 1.09 Ucp3 1.80 2.02 2.79

A study of the expression of 20,341 genes in cardiac tissue revealed that 2,829 genes exhibited statistically significant differences in expression (P<0.01). Of these, 7% (approximately 189 genes) exhibited altered expression in animals subjected only to calorie reduced diets; 8% (approximately 226 genes) exhibited altered expression in animals receiving only resveratrol; no additional genes exhibited altered expression in animals that received resveratrol and which were subjected to calorie reduced diets. In contrast, 61% of the 20,341 genes (approximately 1,729 genes) exhibited altered expression in animals receiving only compounds of the present embodiments (e.g., Longevinex®); an additional 2% of the genes (approximately 56 genes) exhibited altered expression in animals that had received compounds of the present embodiments (e.g., Longevinex®) and which had been subjected to calorie reduced diets; an additional 21% of the genes (approximately 594 genes) exhibited altered expression in animals that had received compounds of the present embodiments (e.g., Longevinex®) and resveratrol; an additional 1% of the genes (approximately 28 genes) exhibited altered expression in animals that had received compounds of the present embodiments (e.g., Longevinex®), resveratrol and which had been subjected to calorie reduced diets.

The above data demonstrates that compounds of the present embodiments (e.g., Longevinex®) were effective in modulating gene expression in heart tissue to an extent surpassing even that of calorie restriction. Similar effects have been observed in non-heart tissue. A study of the expression of 20,341 genes in brain tissue revealed that 3,572 genes exhibited statistically significant differences in expression (P<0.01). Of these, 124 genes exhibited altered expression in animals subjected only to calorie reduced diets; 424 genes exhibited altered expression in animals receiving only resveratrol; 10 genes exhibited altered expression in animals that received resveratrol and which were subjected to calorie reduced diets. In contrast, 2,560 genes exhibited altered expression in animals receiving only compounds of the present embodiments (e.g., Longevinex®); 19 additional genes exhibited altered expression in animals that had received compounds of the present embodiments (e.g., Longevinex®) and which had been subjected to calorie reduced diets; 430 additional genes exhibited altered expression in animals that had received compounds of the present embodiments (e.g., Longevinex®) and resveratrol; 5 additional genes exhibited altered expression in animals that had received compounds of the present embodiments (e.g., Longevinex®), resveratrol and which had been subjected to calorie reduced diets.

Example 4 Model Mechanism of Action of the Compositions of the Present Embodiments

The compounds of the present embodiments were thus found to greatly exceed the modulation of gene expression observed upon calorie restriction and to alter the expression of genes in key pathways of lipid metabolism, glucose metabolism, oxidative phosphorylation, the Kreb's cycle, ATP synthesis and fatty acid beta oxidation. In summary, the compounds of the present embodiments were found to have a greater specific activity than resveratrol alone, both in terms of the number of genes and the number of different biochemical pathways affected. The results are significant since calorie restriction (CR) is considered the unequivocal method of prolonging life in all forms of life. Generally, reduction of 50% of caloric intake doubles the lifespan of any organism. The above-described experiments demonstrate that the compositions of the present embodiments exert a more powerful influence over genome expression than resveratrol or CR, and marks the first time any technology has been shown to exceed the effects of CR. Furthermore, the compositions of the present embodiments were found to influence genome expression at an earlier stage of life than CR (which requires a life-long adherence to a CR diet to differentiate genes).

Without intending to be bound by any mechanism of action, the above results suggest that the compounds of the present embodiments act by enhancing the activity of the forkhead Foxo1 (daf-16, dFoxO) transcription factor (FIG. 4). Studies in model organisms have shown that Foxo1 mediates lifespan expression by enhancing gene expression. Insulin/IGF-1 signaling phosphorylates Foxo1, thereby causing it to be excluded from the nucleus and downregulating its actions. The compounds of the present embodiments decrease insulin and IGF-1 signaling thereby decreasing Foxo1 phosphorylation. Consistent with this model are the observations that the insulin receptor signaling pathway (e.g., GO:008286; genes Ide, Igfbp4, and Igfbp6) is affected by the compounds of the present embodiments. Expression of Foxo1 is increased by 1.75 fold. The compounds of the present embodiments mediate decreased glycolysis and increased gluconeogenesis (e.g., GO:0006006), enhanced Pgc-1α expression (thereby leading to stimulation of Pdk4 expression (e.g., a 1.94 fold increase in Ppargc1α and a 3.25 fold increase in Pdk4), increased expression of lipid metabolism genes (e.g., a 2.79 fold increase in Ucp3, 1.49 fold increase in Cpt1a, and a 1.45 fold increase in Cpt1b). Lipid and fatty acid metabolism genes GO:0006629 and GO:0006635 are uniquely affected by the compounds of the present embodiments. The compounds of the present embodiments thus exert a more pronounced favorable effect on key processes affected by calorie restriction and resveratrol (e.g., chromatin remodeling, transcription from RNA polymerase II promoter, and the ubiquitin cycle. Genes GO:0006333 and GO:0006367 are uniquely affected by the compounds of the present embodiments; Gene GO:0006512 is affected by resveratrol and Longevinex®. Thus, in sum, a proposed mechanism of action is that the compositions of the present embodiments deliver resveratrol to cells, where it passes through cell walls, enters the cytoplasm, and facilitates the translocation of Foxo1 gene into the cell nucleus, which produces the longevity effects.

Example 5 Manufacture and Encapsulation of a Composition of the Present Embodiments

Small molecules in the form of resveratrol were obtained via ethanol extraction from vitis vinifera and polygonum cuspidatum. The ethanol was removed, and the resulting extract comprised approximately 25% vinis vinifera skin resveratrol and 25% polygonum cuspidatum resveratrol, with the remainder comprising non-resveratrol, inert plant material. The biological activity of the resveratrol in the extract was confirmed using a SIRT1 Fluorescent Activity Assay/Drug Discovery Kit AK-555 (available from Biomol® Research Laboratories, Inc.; Plymouth Meeting, Pa.; www.biomol.com). The extract was kept in a nitrogen environment and added to a mixture including approximately 25% by weight quercetin; 33% by weight lecithin; and 9% phytic acid (in the form of rice bran extract). The remainder of the composition included approximately 33% by weight resveratrol extract.

The resulting slurry was placed into a capsule-filling machine. Individual dosages were encapsulated in gelatin capsules tinted with titanium oxide (Licaps® capsules available from Capsugel; Greenwood, S.C.; www.capsugel.com). The dosages were encapsulated in a substantially oxygen-free environment using a capsule-filling machine continually flushed with nitrogen (the Capsugel CFS 1000 Capsule Filling and Sealing Machine, available from Capsugel; Greenwood, S.C.; www.capsugel.com). Each resulting capsule included at least 15 mg resveratrol, 100 mg lecithin, 75 mg quercetin, and 25 mg phytic acid. These capsule samples were stored under ambient conditions for approximately eight months. The samples were tested for biological activity by determining whether each sample could activate sirtuin enzymes and, in particular, whether the samples stimulated SIRT1 catalytic activity. The samples were tested four months and eight months after encapsulation. Tests were performed using a SIRT1 Fluorescent Activity Assay/Drug Discovery Kit AK-555 (available from Biomol® Research Laboratories, Inc.; Plymouth Meeting, Pa.; www.biomol.com). Upon testing, it was determined that the resveratrol contained within the samples was biologically active, stimulating SIRT1 activity, producing up to about an eight-fold stimulation in enzymatic activity compared to when no resveratrol is present. Similarly, the biological activity of the quercetin was tested, and it was determined that the encapsulated quercetin maintained biological activity (i.e., the ability to stimulate SIRT1 activity compared to when no quercetin is present).

Example 6 Comparative Evaluation of Hormetic Action of Resveratrol and the Present Compositions

Numerous studies have conclusively demonstrated the cardioprotective effects of resveratrol, but one significant fact is often neglected—the hormetic action of resveratrol. Resveratrol is a phytoalexin and many plant-derived products display hormesis. Calabrese et al. (2001) Ann Rev Public Health 22:15-33. Hormesis is defined as a dose-response relationship that is stimulatory at low doses, but detrimental at higher doses resulting in a J-shaped or an inverted U-shaped dose response curve. It has been known for quite some time that cardioprotective effects of alcohol or wine intake follow a J-shaped curve. Constant J (1997) Clin Cardiol 20:420-424. An extensive literature search implicated that resveratrol present in red wine also demonstrates a similar health benefits, being highly effective at lower doses and detrimental at higher doses. The present investigation was undertaken to determine a dose-response curve for resveratrol-mediated cardioprotection and to compare this dose-response curve with another commercially available resveratrol supplement, Longevinex® (Resveratrol Partners LLC, USA). The results of the study revealed that while resveratrol displayed hormetic action, Longevinex® did not.

Animals. All animals used in this study received humane care in compliance with the regulations relating to animals and experiments involving animals, and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals (NIH Publication, 1996 edition), and all the protocols were approved by the Institutional Animal Care Committee of University of Connecticut Health Center, Farmington, Conn., USA. Male Sprague-Dawley rats weighing between 250 and 300 g were fed ad libitum regular rat chow with access to water until the start of the experimental procedure. Animals were randomly subdivided in three groups, of which the control group was gavaged with 1 ml of water containing 5% quartering and 5% hydrate and the other two groups were gavaged with either resveratrol or Longevinex®.

Isolated working heart preparation. After completing the feeding protocol, the animals were anesthetized with sodium pentobarbital (80 mg/kg, intraperitoneally) (Abbott Laboratories, North Chicago, Ill., USA), and heparin sodium (500 U/kg, intravenously) (Elkins-Sinn Inc., Cherry Hill, N.J., USA) was used as an anticoagulant. After deep anesthesia, the hearts were excised, the aorta was cannulated, and the hearts were perfused through the aorta in Langendorff mode at a constant (100 cm of water) perfusion pressure at 37° C. with Krebs-Henseleit bicarbonate for a 5 min washout period as described previously. Ray et al. (1999) Free Rad Biol Med 27:160-9. The perfusion medium consisted of a modified Krebs-Henseleit bicarbonate buffer (millimolar concentration: sodium chloride 118, potassium chloride 4.7, calcium chloride 1.7, sodium bicarbonate 25, potassium dihydrogenphosphate 0.36, magnesium sulfate 1.2 and glucose 10), and after its oxygenization pH was 7.4 at 37° C.

During the washout period, the left atrium was cannulated, and the Langendorff preparation was switched to the working mode for 10 min with a left atrial filling pressure of 17 cm H2O; the aortic afterload pressure was set to 100 cm of water. At the end of 10 min, the baseline cardiac function such as heart rate (HR, beats/min), aortic flow (AF, ml/min), coronary flow (CF, ml/min), left ventricular developed pressure (LVDP, mmHg) and first derivative of developed pressure (LVdp/dt, mmHg/sec) were recorded. Later, 30 min of global ischemia was initiated by clamping the left atrial inflow and aortic outflow lines at a point close to their origins. After 30 min, reperfusion was initiated for 120 min by unclamping the atrial inflow and aortic outflow lines. The first 10 min of reperfusion was in Langendorff mode to avoid ventricular fibrillation, and then the hearts were switched to an anterograde working mode. Ray et al. (1999) Free Rad Biol Med 27:160-9.

Cardiac function assessment. After 10 min of the working mode, baseline parameters were recorded. To monitor the recovery of the heart, the left ventricular cardiac function was recorded after 60 and 120 min of reperfusion. Six rats were present in each group. A calibrated flow-meter (Gilmont Instrument Inc., Barrington, Ill., USA) was used to measure the aortic flow. Coronary flow was measured by timed collection of the coronary effluent dripping from the heart. During the entire experiment, the aortic pressure was monitored using a Gould P23XL pressure transducer (Gould Instrument Systems Inc., Valley View, Ohio, USA) connected to the side arm of the aortic cannula; the signal was amplified using a Gould 6600 series signal conditioner (Gould Instrument Systems Inc.). CORDAT II real-time data acquisition and analysis system (Triton Technologies, San Diego, Calif., USA). Dudley et al. (2009) J Nutr Biochem. 20:443-52. The heart rate, left ventricular developed pressure, and the first derivative of developed pressure were all calculated from the continuously generated pressure signal.

Infarct size estimation. Infarct size was measured using the triphenyl tetrazolium chloride (TTC) staining method. Malik et al. (2006) Antioxidant Redox Signal 8:2101-9. After two hours of reperfusion, 40 ml of 1% (w/v) solution of TTC in phosphate buffer was infused into the aortic cannula, and the heart samples were stored at −70° C. for subsequent analysis. Sections (0.8 mm) of frozen heart were fixed in 2% paraformaldehyde, placed between two cover slips and digitally imaged using a Microtek ScanMaker 600z (Microtek, USA). To quantitate the areas of infarct in pixels, a standard National Institutes of Health image program was used. The infarct size was quantified and expressed in pixels.

Cardiomyocyte apoptosis. Immunochemical detection of apoptotic cells was performed using the terminal deoxynucleotidyl transferase-medicated dUTP nick-end labeling (TUNEL) method. Malik et al. (2006) Antioxidant Redox Signal 8:2101-9. The sections were incubated with mouse monoclonal antibody recognizing cardiac myosin heavy chain to specifically detect apoptotic cardiomyocytes. The fluorescence staining was viewed with a confocal laser microscope. The number of apoptotic cells was counted and expressed as a percent of the total myocyte population.

Statistical analysis. The values for myocardial function parameters, infarct size and apoptosis were expressed as the mean±standard error of mean (SEM). A one-way analysis of variance was performed to test for differences in mean values between groups. If differences were established, the values of the drug-treated groups were compared with those of the drug-free group by modified Student's t-test. The results were considered significant if p<0.05.

Effects of different doses of resveratrol on cardioprotection. First, the animals were treated with different doses of resveratrol (2.5 mg/kg, 25 mg/kg and 100 mg/kg) by daily gavaging for 21 days. At the end of the 21 days, the animals were sacrificed, their hearts were excised and isolated, and ischemia was induced for 30 min by terminating the coronary flow (as described in the methods section). This was then followed by 2 h of reperfusion in the working mode; during the reperfusion left ventricular function was monitored. As depicted in FIGS. 5 through 8, resveratrol at doses of 2.5 and 25 mg/kg conferred cardioprotection as evidenced by improved aortic flow, left ventricular developed pressure and maximum first derivative of the developed pressure. Above 25 mg/kg, ventricular function was deteriorated as evidenced by significant reduction of aortic flow, LVDP and maximum LVdP/dt. Above 50 mg/kg (data not shown], especially at 100 mg/kg, there was no aortic flow or developed pressure indicating that the hearts ceased functioning.

At the end of each experiment the hearts were either subjected to TTC staining to determine infarct size or TUNEL staining to detect apoptosis. The results are shown in FIGS. 9 and 10. Resveratrol significantly reduced the myocardial infarct size and cardiomyocyte apoptosis at doses of 2.5 and 25 mg/kg. However, above 50 mg/kg [data not shown at 50 mg/kg], myocardial infarct size and number of apoptotic cardiomyocytes were significant increased, indicating cellular injury

Effects of different doses of Longevinex® on cardioprotection. A parallel experiment was conducted with Longevinex® by gavaging the rats with three different doses of Longevinex® (2.5 mg/kg, 50 mg/kg and 100 mg/kg) for up to one month. The results are shown in FIGS. 5 through 10. Unlike resveratrol, which showed hormesis, Longevinex® displayed the same degree of cardioprotection up to a dose of 100 mg/kg. It is interesting to note that even at a dose as low as 25 mg/kg, Longevinex® could provide the same degree of cardioprotection as depicted in the results of left ventricular function, LVDP, maximum LVdP/dt as well as infarct size and cardiomyocyte apoptosis. The dose-response curves of resveratrol [J-shaped) and Longevinex® (FIG. 9) clearly demonstrate only pure resveratrol and not Longevinex® displayed hormesis.

Because Longevinex® proved to be cardioprotective over a wide range of concentrations, it was further tested on another animal species. A group of New Zealand white rabbits was gavaged with Longevinex® (100 mg/kg) for 6 months, while the control group was given a placebo. After the completion of the feeding protocol, isolated working rabbit hearts were subjected to 30 min of ischemia followed by 2 h of reperfusion. The results of the infarct size are shown in FIG. 12. Cardiac function remained improved for up to 6 months of Longevinex® feeding (Table 10 below), and infarct size and apoptosis remained lowered for the same duration of time.

TABLE 10 Cardiac Function in Control and Longevinex ®-Treated Working Rabbit Hearts 1 month 3 months 6 months Control Treated Control Treated Control Treated Preischemic values HR 234 ± 10 229 ± 10 226 ± 11 231 ± 11 229 ± 9 231 ± 8 CF  68 ± 6  66 ± 6  71 ± 6  70 ± 6  69 ± 8  63 ± 7 AF  94 ± 8  95 ± 8  85 ± 7  87 ± 7  86 ± 8  88 ± 7 LVDP 138 ± 10 139 ± 10 130 ± 9 121 ± 10 131 ± 12 136 ± 8 After 60 min reperfusion HR 217 ± 9 223 ± 9 222 ± 9  218 ± 9 214 ± 9   218 ± 12 CF  48 ± 6  55 ± 4  55 ± 6  66 ± 5*  52 ± 6  63 ± 4* AF  41 ± 9  43 ± 8  42 ± 9  58 ± 6*  38 ± 8  47 ± 4* LVDP  87 ± 8  91 ± 6  91 ± 7 102 ± 7  75 ± 7  85 ± 7* After 120 min reperfusion HR 199 ± 10 195 ± 9 199 ± 9  206 ± 10 200 ± 9 204 ± 12 CF  42 ± 5  44 ± 5  47 ± 5  58 ± 6  48 ± 5  60 ± 7* AF  21 ± 6  28 ± 7  23 ± 7  39 ± 5*  17 ± 5  33 ± 6* LVDP  62 ± 5  65 ± 7  64 ± 6  77 ± 5*  56 ± 5  69 ± 8* Data are presented as mean ± SEM (six rabbits per group). *P < 0.05 compared with the values of the control ischemia (IS)/reperfusion (RE) group. HR = heart rate (beats/min); CF = coronary flow (ml/min); AF = aortic flow (ml/min); LVDP = left ventricular developed pressure (mm Hg).

The results of the present study clearly demonstrate that resveratrol is beneficial to the heart only at low doses, and is detrimental at higher doses. Also, the action of resveratrol is quickly realized, in most cases within 14 days to 30 days; prolonged resveratrol use does not add any additional benefit. However, we did not study whether prolonged use of resveratrol could cause any adverse effects. Such hormetic effects have been known for more than 100 years, and frequently observed among toxins. Resveratrol is a phytoalexin, whose growth is stimulated by environmental stress such as fungal infection, UV radiation and water deprivation. Adrian et al. (1996) J Agri Food Chem 44:1979-81.

The cardioprotective effects of resveratrol are exerted through its ability to precondition a heart, which causes the development of intracellular stress leading to the upregulation of intracellular defense system such as antioxidants and heat shock proteins. Wallerath et al. (2002) Circulation 106:1652-1658. Preconditioning is another example of hormesis, which is potentiated by subjecting an organ (such as the heart) to cyclic episodes of short durations of ischemia, each followed by another short duration of reperfusion. Das et al. (2003) Arch Biochem Biophys. 420:305-311. Such small but therapeutic amounts of stress render the heart resistant to subsequent lethal ischemic injury. Such an adaptive response is commonly observed with aging. Consistent with this idea, resveratrol has been found to stimulate longevity genes, and at least in prokaryotic species extends the life span. Mukherjee et al. (2009) Free Rad Biol Med 46:573-578; Wood et al. (2008) Nature 7:63-78. In this respect, resveratrol may fulfill the definition of a hormetin. Rattan (2008) Aging Res Rev 7:63-78.

There is no doubt that alcohol, wine, and wine-derived resveratrol all display hormesis. It is known that cardioprotective effects of alcohol or wine intake follow a J-shaped curve, Calabrese et al. (2001) Ann Rev Public Health 22:15-33 and Constant J (1997) Clin Cardiol 20:420-424, and the present study echoed this finding (FIG. 11). At lower doses, resveratrol acts as an anti-apoptotic agent, providing cardioprotection as evidenced by increased expression in cell survival proteins, improved post-ischemic ventricular recovery and reduction of myocardial infarct size and cardiomyocyte apoptosis by maintaining a stable redox environment compared with control. At higher doses, however, resveratrol depresses cardiac function, elevates levels of apoptotic protein expressions, results in an unstable redox environment, and increases myocardial infarct size and the number of apoptotic cells. A significant number of reports are available in the literature to show that at a high dose, resveratrol not only hinders tumor growth but also inhibits the synthesis of RNA, DNA and protein; causes structural chromosome aberrations, chromatin breaks, chromatin exchanges, weak aneuploidy, higher S-phase arrest; blocks cell proliferation; decreases wound healing, endothelial cell growth by fibroblast growth factor-2 (FGF-2) and vascular endothelial growth factor (VEGF); and inhibits angiogenesis in healthy tissue cells leading to cell death. Dudley et al. (2009) J Nutr Biochem. 20:443-52.

Longevinex® was tested side-by-side to the pure resveratrol. Longevinex® did not show any hormetic action (cytotoxicity) up to a dose of 100 mg/kg. It should be noted that any dose of pure resveratrol over 50 mg/100 g stops the heart. Dudley et al. (2009) J Nutr Biochem. 20:443-52. We also determined the long-term effect of Longevinex® on different species of animals, e.g., rabbits, and found that even after 6 months of treatment, Longevinex® provided cardioprotection. The results found in the present study are important for scientists, clinicians and the nonmedical community because it highlights the importance of using resveratrol alone only at lower doses because harmful or toxic effects can occur at higher doses, resulting in adverse effects on health. Longevinex®, however, did not exhibit harmful or toxic side effects at low or high doses. Epidemiological and clinical trials need to be based on the clear understanding of hormetic beneficial effects of resveratrol.

Example 7 Restoration of Altered MicroRNA Expression in the Ischemic Heart with Compositions of the Present Embodiments

As reported by Mukhopadhyay P, Mukherjee S, Ahsan K, Bagchi A, Pacher P, and Das D, cardiprotection by resveratrol and its derivative in ischemia/reperfusion [I/R] rat model was examined with miRNA expression profile. Mukhopadhyay et al. (2010) Restoration of Altered MicroRNA Expression in the Ischemic Heart with Resveratrol. PLoS ONE 5(12): e15705. doi:10.1371/journal.pone.0015705. A unique expression pattern were found for each sample, particularly with Longevinex®, a commercially available resveratrol supplement of the present embodiments available from Resveratrol Partners LLC, USA. Longevinex® and resveratrol pretreatment modulated the expression pattern of miRNAs close to the control level based on PCA analyses. Differential expression was observed in over 50 miRNAs, some of them, such as mir21 were previously implicated in cardiac remodeling. The target genes for the differentially expressed miRNA include genes of various molecular function such as metal ion binding, sodium-potassium ion, transcription factors, which may play a key role in restricting the damage in the heart.

As discussed below in more detail, Longevinex® in particular exerted a much greater influence over microRNAs miR-539 and miR-20b than plain resveratrol. These two microRNAs control VEGF and HIF-1 genes involved in neovascularization, suggesting therapeutic applications with respect to wet macular degeneration, any neovascular eye disease (glaucoma), diabetic retinopathy, and in particular, cancer.

Results and Discussion: Resveratrol and Longevinex® improve cardiac function and reduce myocardial infarct size and cardiomyocyte apoptosis in the IR rat heart. In accordance with previous studies, both resveratrol and Longevinex® improved cardiac output function including aortic flow, coronary flow, left ventricular developed pressure (LVDP) and its first derivative LV_(max) dp/dt 2 hour of reperfusion period (FIG. 13). Gurusamy et al., Cardiovasc. Res. 86:103-112 (2010). FIG. 13 depicts the effects of resveratrol and Longevinex on aortic blood flow (FIG. 13A), coronary flow (FIG. 13B), LVDP (FIG. 13C), dp/dt_(max) (FIG. 13D), infarct size (FIG. 13E), and apoptosis (FIG. 13F). Coronary flow, aortic flow and LVDP were estimated at baseline and at the indicated times of reperfusion. Infarct size and apoptosis were measured at the end of two hours of reperfusion. Results are expressed as Means plus/minus SEM of six animals per group. *p<0.05 vs. Vehicle (VEH). #p<0.05 vs corresponding I/R. BL: Baseline; I/R1h: Ischemia for 30 min and 1 h reperfusion; I/R2h: Ischemia for 30 min and 2 h reperfusion; RESV: Resveratrol; LONG: Longevinex®.

These compounds also lowered the infarct size and death due to cardiomyocyte apoptosis, as expected. A significant number of studies exist in the literature demonstrating cardioprotective role of resveratrol. Recent studies also showed that commercially available resveratrol formulation Longevinex® was equally cardioprotective. We compared the effects of resveratrol with Longevinex®, because recent studies determined Longevinex® to be equally cardioprotective without exhibiting hormetic action of resveratrol, and found that the cardioprotective effects of resveratrol and Longevinex® were consistent with the previously published reports by Mukherjee et al., J. Exp. Clin. Cardiology (in press).

Global miRNA expression profiling in ischemia-reperfused rat heart. MicroRNA profiles were analyzed by TLDA array specific for 586 miRNA and five endogeneous control for rat. Array were carried out in six different groups namely basal level (BL): (1) control vehicle, (2) Resveratrol, (3) Longevinex®, and ischemic repurfused (IR): (4) control vehicle I/R, (5) pretreated (21 days) with Resveratrol I/R and (6) pretreated (21 days) with Longevinex® I/R. RNAs were isolated after 30 min ischemia and 2 hour reperfusion of the heart from IR samples or from baseline (BL) samples processed the same way without ischemia and reperfusion.

FIG. 14A is a box Whisker plot demonstrating unique distribution of total miRNA expression for all samples. The box whisker plot shows the median in the middle of the box, the 25th percentile (lower quartile) and the 75th percentile (the upper quartile). The whiskers are extensions of the box, snapped to the point within 1.5 times the interquartile. The points outside the whiskers are plotted as they are and considered the outliers and excluded for analysis. The data (Ct values) were normalized based on endogenous genes. Few miRNA were observed to be outliers and 385 miRNA out of 586 were observed to be expressed at least in one of the six conditions. FIG. 14B is a profile plot showing expression of 385 miRNA after normalization to endogeneous control for each samples. miRNA expression were further analyzed by transforming to “fold change” compared to basal level control sample. BL: Baseline; I/R2h: Ischemia for 30 min and 2 h reperfusion; VEH: Vehicle, RESV: Resveratrol; LONG: Longevinex®.

Expression of 213 miRNA were expressed at least 2 fold or higher under one of six conditions. The list was further filtered after looking into miRNA which were either up or down 2-fold in IR samples. Top 25 miRNA were listed, which were either up or down regulated in IR condition (Table 11) and the most regulations were reversed by pretreatment with resveratrol and Longevinex®. IR samples pretreated with resveratrol and Longevinex® both reversed the up or down regulation in IR Control in the opposite direction in 11 of the 25 miRNAs listed in Table 11. Either resveratrol or Longevinex®, but not both, reversed the up or down regulation compared to IR control in 5 instances. In rest of 9 miRNAs expression were attenuated by either or both.

TABLE 11 Differential Expression Of MicroRNA Expressed In Fold Change With Respect To Basal Level Control Heart Sample BL BL IR IR miRNA Resveratrol Longevinex ® IR Control Resveratrol Longevinex ® miR-539 up 1272.9 up 642.7 up 214.3 up 172.4 up 314.6 miR-27a up 2.2 up 2.1 up 9.3 up 5.5 up 1.4 miR-101a up 28.4 up 39.2 up 6.1 up 3.1 up 3.3 miR-9 up 2.6 up 1.1 up 5.4 down 1.7 down 1.1 miR-667 up 8.2 up 6.3 up 4.4 up 2 up 1.2 miR-339-5p up 13.6 up 20.7 up 4.1 down 1.4 down 3.8 rno-miR-345- up 40.8 up 23.1 up 3.7 down 12 down 1.1 3p miR-10a up 6.4 up 5.2 up 3.5 down 116 down 1.6 snoRNA202 up 3.8 up 4.7 up 3.2 down 6 down 3 miR-27b down 1.4 up 1.9 up 3.2 up1 up1 miR-29c up 5.4 up 4.5 up 3.1 up 1.5 down 1.5 miR-345-5p up 14.3 up 31.7 up 2.4 down 4.7 1.1 rno-miR-24-1 down 25.3 up 1.2 up 2.1 down 1.2 down 1.9 miR-687 up 3.8 up 1.8 up 2 down 1.7 down 11.5 miR-27a up 34 up 12.8 up 1.6 down 1.7 up 1.5 miR-31 up 2.4 up 1.1 up 1.6 down 17.5 down 2.1 miR-20b down 6 down 38.8 down 112.9 down 189 down 1366 miR-760 down 2.7 up 2.5 down 30.8 up 1.5 up 2.2 miR-351 up 3.9 up 9.1 down 20.9 down 1.3 up 1.9 miR-181c up 5.3 up 4.2 down 6.7 up 1.4 down 9.1 miR-21 up 391.4 up 760.9 down 4 up 61.5 up 59.3 miR-25 up 25 up 11.5 down 1.9 up 1.1 up 4.2 rno-miR-450a up 4.8 up 2.4 down 1.7 down 1.5 down 5.4 miR-214 up 4.2 up 6.2 down 1.3 down 3.9 down 6.5 miR-324-3p up 4.9 up 6.5 down 1.2 down 5.6 down 5.3

Longevinex® exceeded the effect of resveratrol in 15 of the 25 miRNAs including miR-10a, miR-20b, miR-21. However, in few miRNAs such as miR-29c, Longevinex® had an opposing effect to resveratrol and the difference may be due to many possibilities including presence of other ingredients in Longevinex®, bio-availability of resveratrol etc. There was a tremendous upregulation of miR-21 expression in basal level controls with resveratrol (up 391.4) and Longevinex® (760.9) which was lowered considerably in IR (up 61.5 and 59.3). miR-539 is upregulated to high level (214 fold) in IR samples and was further up-regulated in resveratrol pretreated samples. Similar observations were also found in miR-27a, miR-101, miR-9, miR-667. Similar but less pronounced change were also found in many other miRNAs.

FIG. 15 depicts the effects of resveratrol and Longevinex® on miRNA expression pattern. FIG. 15A depicts the correlation of miRNA expressions between basal level and IR control heart using a scatter plot. Few miRNA expressions were selected for display as shown in Table 11. Double lines indicate as fold change of 2. FIG. 15B depicts a heatmap for cluster analyses of differentially expressed miRNA among samples: Each miRNA was represented as single bar based from their Ct values and color coding was shown below with a gradient from blue (negative and lowest Ct values) to red (positive and highest Ct values). miRNAs not detected were shown as black bars. Each column was represented sample indicated on top. It is evident from the heatmap that treatment with either resveratrol or Longevinex® in control samples altered significant miRNA expression levels, some of them may play significant key roles in cardio-protection. FIG. 15C illustrates principal component analyses of all samples. This multivariate analysis demonstrated the proximity of Longevinex® and resveratrol treated IR samples to the control (vehicle) samples. Principal component analyses of the six samples revealed that the samples IR Longevinex® and IR resveratrol were remarkably similar to BL vehicle sample in terms of gene expression. In the majority of cases, they also were readily distinguished from each group. These results are indeed of utmost importance, as they document that both resveratrol and Longevinex® can protect the ischemic heart by restoring the IR-induced up-regulation or down-regulation of gene expression. BL: Baseline; IR: Ischemia for 30 min and 2 h reperfusion; VEH: Vehicle, RESV: Resveratrol; LONG: Longevinex.

miR-539, the highest upregulated miRNA has 271 conserved gene targets however its functional target has not been reported in the literature. The targets of miR-539 obtained by computational analyses include matrix metallopeptidase 20, fibroblast growth factor 14, clathrin, light polypeptide, osteoprotegerin and transcription factors like forkhead box B1, which may have roles in cardiac remodeling. miR-21 were shown to regulate the ERK-MAP kinase signaling pathway in cardiac fibroblasts, which has role on global cardiac structure and function. Thum et al., Nature 456:980-986 (2008). It has been also shown earlier that resveratrol triggers MAPK signaling pathway as a preconditioning mechanism in heart. Das et al., J. Pharmacol. Exp. Ther. 317:980-988 (2006). We also looked in samples in the ERK-MAPK pathway. As shown in FIG. 16A, ERK phosphorylation was observed to be increased in both resveratrol and Longevinex® treated baseline samples and reduced in corresponding IR samples. In FIG. 16A, the ratio of ERK1/2 phosphorylation to total ERK1/2 were plotted in samples as indicated. A similar but opposing effect was observed in p38 phosphorylation where significantly less phosphorylation occurred in resveratrol or Longevinex® treated BL samples, as depicted in FIG. 16B. Increased p38 MAPK phosphorylation occurred in I/R2h samples and attenuated in both resveratrol and Longevinex® treated I/R2h samples due to preconditioning. In FIG. 16B, the ratio of p38 MAPK phosphorylation to total p38 MAPK were plotted in samples as described. Results are expressed as Means plus/minus SEM of six animals per group. *p<0.05 vs. Vehicle (VEH). #p<0.05 vs corresponding I/R. BL: Baseline; I/R2h: Ischemia for 30 min and 2 h reperfusion; RESV: Resveratrol; LONG: Longevinex®.

VEGF is modulated by miR-20b through HIF1a in cardiomycytes whereas FOXO1 is regulated by miR-27a in cancer cells. Cascio et al., J. Cell Physiol. 224:242-249 (2010); Guttilla et al., J. Biol. Chem. 284:23204-23216 (2009); Tang et al., Cell Death and Differentiation (2008) 15:667-671. SIRT1 were observed to be regulated by miR-9 in stem cells. Saunders et al., Aging (2010). Recent studies demonstrated the increase of miR-1 in coronary artery diseases (CAD) and miR-1 is downregulated by beta-blocker propranolol in rat model of myocardial infarction. Lu et al., Cardiovasc. Res. 84:434-441 (2009). Specific modulations of microRNA by resveratrol have not shown in any in vivo models. Recently microarray analysis of the effect of resveratrol has been demonstrated in human acute monocytic leukemia cell line (THP-1) and human colon adenocarcinoma cell line (SW480). Tili et al. Biochem. Pharmacol. 80:2057-2065 (2010); Tili et al., Carcinogenesis 31:1561-1566 (2010). Resveratrol decreases the levels of miR-155 in THP-1 and modulating JunB and JunD, key regulators in carcinogenesis. Resveratrol also modulates microRNA targeting effectors of TGFbeta pathways. Id. Treatment with resveratrol in cancer cell line SW480 results in decreased level of miR-21 and miR29c whereas it was increased in healthy heart when treated with resveratrol. Id. This anomaly may be due to the fact that cardiomyocytes is barely dividing cells whereas SW480 cells grow rapidly which leads to complete different microenvironment inside cells. It is also important to point out that the doses for resveratrol is much higher (50 micromolar) in cancer cells and similar dose is partially detrimental to human cardiomyocytes and endothelial cells in cultures (data not shown).

Integrative analyses of miRNA for target gene and pathway analyses. Differentially expressed miRNAs were further analyzed for their putative target genes using TargetScan and were listed in Table 12.

TABLE 12 Putative Target Genes for Differentially Expressed miRNA Molecular Function Number of Category Target Genes Examples of Target Genes RNA binding 101 Snrpe, Cherp, Phax Actin binding 40 Tnni1, Cald1, Cfl1 Signal transducer activity 10 Gnb1, Wnt16 Receptor activity 55 Gpr155, Mmd2, Gab2 Structural molecule activity 31 Lmnb1, Krt1 Calcium ion binding 109 Ocm, Calm1, Rad21 Oxidoreductase activity 52 Duox2, Aldh2, Gpx7 Phosphatase activity 51 Mtmr1, Ptpn1, Styx Potassium ion binding 50 Kcnc1, Slc12a4 Sodium ion binding 54 Scn4a, Hcn1 Chloride ion binding 40 Ano1, Ano1 Sequence-specific DNA 186 Foxo1, Traf3, Dnmt3b binding Metal ion binding 1237 Dnmt3b, Rarb, Kcnd1

Most of the target genes (>1400 genes) have molecular function of metal ion binding, calcium-potassium-chloride ion binding, correlated to the restructuring heart after IR damage. Importantly, miRNA target gene modulated sequence specific DNA factor such as FOXO1, TRAF3 etc. SirT1 regulates several transcription factors including FoxO1, which is inactivated by phosphorylation via Akt. Brunet et al., Science 303:2011-2015 (2004). Recent publication showed the phosphorylation of FoxO1 along with the activation of SirT1, SirT3 and SirT4 are localized in mitochondria where they regulate aging and energy metabolism. Mukherjee et al., Free Radic. Biol. Med. 46:573-578 (2009). Over the years, SIRT1 was known to be activated by resveratrol. Baxter et al., J. Cosmet. Dermatol. 7:2-7. However, resveratrol may have no direct roles in activating SIRT1 Pacholec et al., J. Biol. Chem. 285:8340-8351 (2010). Since dysregulation of miRNAs such as miR-21 is directly linked with cardiac diseases like ischemic heart disease and since resveratrol can ameliorate myocardial ischemic reperfusion injury through the modulation of several miRNAs, the results of the present study explains the mechanism of complex regulatory network mediated by resveratrol through miRNA in cardioprotection.

In summary, microRNA regulate target gene mostly by translational repression and sometimes through translational activation. Here, we demonstrated that resveratrol or Longevinex® regulated miRNA expression in healthy heart and ischemic-reperfused heart. Future detailed studies based on these analyses will pave the way for development of novel therapeutic intervention for cardioprotection in acute I/R injury.

Methods. Animals. All animals used in this study received humane care in compliance with the regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NIH Publication, 1996 edition, and all the protocols (Proposal #2008-484) were approved by the Institutional Animal Care Committee of University of Connecticut Health Center, Farmington, Conn., USA. Male Sprague-Dawley rats weighing between 250 and 300 g were fed ad libitum regular rat chow with free access to water until the start of the experimental procedure. Animals were gavaged with either resveratrol (5 mg/kg/day) [Sigma Chemical Company, St. Louis, Mo.] or Longevinex® (100 mg/kg/day) for 21 days. Previous studies from our laboratory established the appropriate dose and time periods for each compound used in this experiment. Hattori et al., Am. J. Physiol. Heart. Circ. Physiol. 282:H1988-1995 (2002); Mukherjee et al., Can. J. Pharmol. Physiol. 2010 November; 88(11):1017-25.

Isolated working heart preparation and assessment of cardiac function. After completing the feeding protocol, the animals were anesthetized with sodium pentobarbital (80 mg/kg, i.p.) (Abbott Laboratories, North Chicago, Ill., USA), and intraperitoneal heparin sodium (500 IU/kg, i.v.) (Elkins-Sinn Inc., Cherry Hill, N.J., USA) was used as an anticoagulant. After the deep anesthesia was conformed, hearts were excised, the aorta was cannulated, and the hearts were perfused through the aorta in Langendorff mode at a constant (100 cm of water) perfusion pressure at 37 C with the KHB for a 5 min washout period as described previously. The perfusion medium consisted of a modified Krebs-Henseleit bicarbonate buffer (millimolar concentration: sodium chloride 118, potassium chloride 4.7, calcium chloride 1.7, sodium bicarbonate 25, potassium dihydrogen phosphate 0.36, magnesium sulfate 1.2 and glucose 10), and after its oxygenization pH was 7.4 at 37 C. During the washout period left atria was cannulated, and the Langendorff preparation was switched to the working mode for 10 min with a left atrial 6 filling pressure of 17 cm H₂O, aortic afterload pressure was set to 100 cm of water. At the end of 10 min, baseline cardiac function like heart rate (HR, beats/min), aortic flow (AF, ml/min), coronary flow (CF, ml/min), left ventricular developed pressure (LVDP, mmHg) and first derivative of developed pressure (LVdp/dt, mmHg/sec) were recorded. After that 30 min of global ischemia was initiated by clamping the left atrial inflow and aortic outflow lines at a point close to their origins. At the end of the 30 min of ischemia, reperfusion was initiated for 60 min or 120 min by unclamping the atrial inflow and aortic outflow lines. The first 10 min reperfusion was in Langendorff mode to avoid the ventricular fibrillations, after the hearts were switched to anterograde working mode. Mukherjee et al., Free Radic. Biol. Med. 46:573-578 (2009).

Infarct size estimation. Infarct size was measured according to the TTC method. Mukherjee et al., Free Radic. Biol. Med. 46:573-578 (2009); Imamura et al., Am. J. Physiol. Heart Circ. Physiol. 282:H1996-2003 (2002). After the 2 h of reperfusion, 40 ml of 1% (w/v) solution of triphenyl tetrazolium chloride (TTC) in phosphate buffer was infused into aortic cannula, and the heart samples were stored at −70 C for subsequent analysis. Sections (0.8 mm) of frozen heart were fixed in 2% paraformaldehyde, placed between two cover slips and digitally imaged using a Microtek ScanMaker 600z. To quantitate the areas of infarct in pixels, standard NIH image program was used. The infarct size was quantified and expressed in pixels. Mukherjee et al., Free Radic. Biol. Med. 46:573-578 (2009); Imamura et al., Am. J. Physiol. Heart Circ. Physiol. 282:H1996-2003 (2002).

Assessment of apoptotic cell death. Immunohistochemical detection of apoptotic cells was carried out using the TUNEL method (Promega, Madison, Wis.). Mukherjee et al., Free Radic. Biol. Med. 46:573-578 (2009); Imamura et al., Am. J. Physiol. Heart Circ. Physiol. 282:H1996-2003 (2002). Briefly, after the isolated heart experiments the heart tissues were immediately put in 10% formalin and fixed in an automatic tissue fixing machine. The TUNEL staining was performed according to the manufacturer's instructions. The fluorescence staining was viewed with a fluorescence microscope (AXIOPLAN2 IMAGING, Carl Zeiss Microimaging Inc., New York) at 520620 nm for green fluorescence of fluorescein and at 620 nm for red fluorescence of propidium iodide. The number of apoptotic cells was counted and expressed as a percent of total myocyte population.

Micro RNA isolation and cDNA preparation. Total RNA from rat heart samples were isolated using Trizol reagent (Invitrogen) and further purified using mirVANA miRNA isolation kit (Ambion). Mukhopadhyay et al., Am. J. Physiol. Heart Circ. Physiol. 296:H1466-1483 (2009). cDNAs were prepared using Taqman miRNA Reverse Transcription kit and Megaplex Rodent Pool A and B primers sets.

Profiling of miRNA expression. miRNA expression profiling were carried out using quantitative real-time PCR method by TaqManH Gene Signature Rodent Arrays on a 384 well micro fluidic card in 7900HT Realtime PCR machine (Applied Biosystem, Foster City) according to manufacturer's recommendation. Each miRNA were quantified by two specific amplicon primers and one specific probe. Comprehensive coverage of Sanger miRBase v10 was enabled across a two-card set of TaqManH MicroRNA Low Density Arrays (TLDA Array A and B) for a total of 518, and 303 unique assays, specific to rat miRNAs, respectively. In addition, each array contains six control assays—five carefully selected candidate endogenous control assays, and one negative control assay. Profiling of miRNA by array has been used previously. Chen et al., BMC Genomics 10:407 (2009).

Analyses of miRNA gene expression data. Realtime PCR data expressed as Ct values from array A and B were combined using R script (provided by GeneSpring Informatics Support Team) and processed using GeneSpringGX 11.0.2 software (Agilent Technologies, Santa Clara). After analysis 591 entities were detected from array A and B. All statistical analyses including normalization to endogeneous control, quality control, filtering, correlation analyses and principal component analyses were carried out by GeneSpring GX software.

miRNA Target prediction. miRNA targets have been predicted using TargetScan in-built and plugged within GeneSpring GX software.

Western Blot analysis. Hearts were homogenized in a buffer containing 25 mM Tris-HCl, 25 mM NaCl, 1 mM orthovanadate, 10 mM NaF, 10 mM pyrophosphate, 10 mM okadaic acid, 0.5 mM EDTA, and 1 mM phenylmethylsulfonyl fluoride. One hundred micrograms protein of each heart homogenates separated by SDS-polyacrylamide gel electrophoresis and immobilized on polyvinylidene difluoride membrane. The membrane was immune-blotted with ERK1/2, phospho-ERK1/2, p38 MAPK and phospho-p38 MAPK (Cell signaling Technology, MA) to evaluate the phosphorylation of the compounds. The resulting blots were digitized and subjected to densitometric scanning using a standard NIH image program.

Statistical analysis. The values for myocardial function parameters, infarct size and apoptosis were expressed as the mean±standard error of mean (SEM). A one-way analysis of variance was first carried out to test for any differences in mean values between groups. If differences were established, the values of the resveratrol-treated groups were compared with those of the control group by modified t-test. The results were considered significant if p>0.05.

Example 8 Anti-Angiogenic Action in the Ischemic Myocardium with Compositions of the Present Embodiments

As reported by Mukhopadhyay P, Das S, Gorbunov N, Otani H, Pacher P, and Das D, a study was designed to examine the effects of resveratrol and Longevinex® with or without γ-tocotrienol in the ischemic myocardium on hemodynamic functions and angiogenic factors VEGF and HIF-1α. Mukhopadhyay et al., Modulation of MicroRNA 20b with Resveratrol and Longevinex is Linked with Potent Anti-Angiogenic Action in the Ischemic Myocardium: Synergistic Effects of Resveratrol and Gamma-Tocotrienol (in press). Results demonstrated that Longevinex® indeed possesses potent anti-angiogenic action on the heart, which corroborated with its ability to down-regulate VEGF and HIF-1α. Antagomir specific for miRNA 20b reversed the anti-angiogenic action of Longevinex®.

Effects of antagomir-20b on resveratrol, Longevinex® and γ-tocotrienol induced expression of HIF-1α and VEGF. The results for the expression of HIF-1α and VEGF are shown in FIGS. 17 and 18.

FIGS. 17A through 17C are bar graphs (top) quantifying the results of Western blots (bottom) depicting the regulation of miR-20b and the effects of antagomiR-20b on VEGF. FIG. 17A depicts VEGF Western blot analysis and its quantification of the experimental groups are (1) IR sham (vehicle), (2) IR+γ-tocotrienol, (3) IR+resveratrol, (4) IR+γ-tocotrienol+resveratrol, and (5) IR+Longevinex®. *p<0.05 vs IR Sham where n=4/group. FIG. 17B depicts VEGF western blot analyses and its quantification of the same group of samples when pretreated with antagomiR-20b. *p<0.05 vs IR Sham where n=4/group. FIG. 17C depicts Taqman Real-time PCR quantification of the same samples.

FIGS. 18A and 18B are bar graphs (top) quantifying the results of Western blots (bottom) depicting the regulation of miR-20b and the effects of antagomiR-20b on HIF-1a expression. FIG. 18A depicts HIF-1a Western blot analysis and its quantification of the experimental groups (1) IR sham (vehicle), (2) IR+γ-tocotrienol, (3) IR+resveratrol, (4) IR+γ-tocotrienol+resveratrol, and (5) IR+Longevinex®. FIG. 18B depicts HIF-1a Western blot analyses and its quantification of the same group of samples when pretreated with antagomiR-20b. *p<0.05 vs IR Sham where n=4/group.

Animals. All animals used in this study received humane care in compliance with the regulations relating to animals and experiments involving animals and adheres to principles stated in the Guide for the Care and Use of Laboratory Animals, NIH Publication, 1996 edition, and all the protocols (Proposal #2008-484) were approved by the Institutional Animal Care Committee of University of Connecticut Health Center, Farmington, Conn., USA. Male Sprague-Dawley rats weighing between 250 and 300 g were fed ad libitum regular rat chow with free access to water until the start of the experimental procedure. Animals were gavaged with either resveratrol (5 mg/kg/day) [Sigma Chemical Company, St. Louis, Mo.] or Longevinex® (100 mg/kg/day) or γ-tocotrienol [5 mg/kg/day], alone or in combination with resveratrol [5 mg/kg/day] for 21 days. Previous studies from our laboratory established the appropriate dose and time periods for each compound used in this experiment. Hattori et al., Am. J. Physiol. Heart. Circ. Physiol. 282:H1988-1995 (2002); Mukherji et al., Can. J. Pharmol. Physiol. (in press).

Effects of Antagomir miR-20b on the Cardioprotection and the Expression of HIF-1α and VEGF. Because interventions including the treatments with resveratrol, Longevinex® and γ-tocotrienol indicated several-fold upregulation of miRNA 20b, antagomir mirRNA20b was used to specifically examine the role of miRNA 20b on the cardioprotective effects of these compounds. The animals were treated with antagomir miRNA20b [i.v.]. 72 h prior to the experiment. After 72 h, all animals were sacrificed and myocardial function was determined and Western blot analysis was performed. Western blot analysis for HIF-1α and VEGF: The effects of resveratrol, Longevinex® and γ-tocotrienol on the expression of HIF-1α and VEGF were estimated by Western blot analysis using antibodies against VEGF and HIF-1α.

The results shown in FIGS. 17 and 18 indicate that both HIF-1α and VEGF expressions are significantly downregulated after the treatment. For VEGF, when γ-tocotrienol was used in conjunction with resveratrol, there was further reduction of VEGF expression, suggesting synergistic action. Longevinex® resulted in very significant reduction of VEGF expression, far greater than resveratrol and γ-tocotrienol. HIF-1α expression was also reduced with the treatments; however, there were no intergroup differences for reservation and γ-tocotrienol. Again, Longevinex® displayed greater reduction [compared to resveratrol and γ-tocotrienol] of HIF-1α Antagomir miRNA20b restored the expressions of both VEGF and HIF-1α for all the treatments suggesting that expressions of VEGF and HIF-1α are dependent of miRNA 20b.

Modulation of miR-20b in ischemic heart and reversed with resveratrol and γ-tocotrienol. Consistent with the results of Western blots, miR-20b was shown to be modulated drastically in ischemia ischemia-reperfused rat heart. miR-20b significantly down regulated in I/R heart as quantified with Taqman real-time PCR (FIG. 17C). A down regulation (9.8 fold) of mir-20b is reversed to 9.4, 8.2, 15.2 and 27.5 fold in γ-tocotrienol, resveratrol, resveratrol+γ-tocotrienol and Longevinex® pretreated I/R hearts respectively. miR-20b targets HIF1α and modulates VEGFα expression.

The effects of resveratrol, Longevinex® and γ-tocotrienol on intracellular reactive oxygen species (ROS) activity. Intracellular ROS activity determined by monitoring the level of fluorescence by measuring the fluorescent oxidation product CM-DCF in the cytosol is shown in FIG. 19. FIG. 19 is a bar graph depicting the Intracellular quantification of reactive oxygen species by DCFDA in the experimental groups (1) IR sham (vehicle), (2) IR+γ-tocotrienol, (3) IR+resveratrol, (4) IR+γ-tocotrienol+resveratrol, and (5) IR+Longevinex®. *p<0.05 vs IR Sham where n=4/group. All the compounds including γ-tocotrienol, resveratrol and Longevinex® lowered intracellular ROS concentration compared to control. However, there was no difference between the groups.

Because resveratrol functions by changing ischemia/reperfusion-mediated harmful oxidative environment into a reduced environment, intracellular ROS concentration was determined with CM-H₂DCFDA [5-(and-6)-chloromethyl-2′,7′-dichlorodihydrofluorescein di-acetate, acetyl ester][10 μM; Molecular Probes, Eugene, Oreg.], a derivative of DCF-DA, with an additional thiol reactive chloromethyl group, which enhances the ability of the compound to bind to intracellular components, thereby prolonging the dye's cellular retention. The dye was injected intravenously, prior to induction of ischemia/reperfusion, and at the end of the experiments, the level of fluorescence was determined for the generation of ROS by measuring the fluorescent oxidation product CM-DCF in the cytosol, at an excitation wavelength of 480 nm and an emission wavelength of 520 nm.

Interestingly enough, the Longevinex® composition showed more potent cardioprotective action and more potent anti-angiogenic effects on heart as evidenced by the down-regulation of VEGF and HIF-1α. The results of resveratrol were compared with the Longevinex® composition, and it was determined that Longevinex® exhibited downregulation of VEGF and HIF-1α, and also showed many-fold induction of microRNA 20-b (a potent anti-angiogenic factor) as compared to that for resveratrol.

All publications and patents mentioned in this specification are herein incorporated by reference to the same extent as if each individual publication or patent application was specifically and individually indicated to be incorporated by reference in its entirety. While the embodiments has been described in connection with specific embodiments thereof, it will be understood that it is capable of further modifications and this application is intended to cover any variations, uses, or adaptations of the embodiments following, in general, the principles of the embodiments and including such departures from the present disclosure as come within known or customary practice within the art to which the embodiments pertains and as may be applied to the essential features hereinbefore set forth.

TABLE 3 CO CR RES Lgx Fold Change Probe Set ID mean mean mean mean CR RES LGX 1415670_at 987 1139 1187 1378 1.15 1.20 1.40 1415671_at 2454 2539 2030 2071 1.03 −1.21 −1.19 1415672_at 3213 2819 2637 2262 −1.14 −1.22 −1.42 1415677_at 706 747 933 934 1.06 1.32 1.32 1415679_at 4825 4129 3776 3154 −1.17 −1.28 −1.53 1415684_at 638 573 490 381 −1.11 −1.30 −1.67 1415696_at 6629 7063 5491 5988 1.07 −1.21 −1.11 1415700_a_at 5461 5179 3791 2603 −1.05 −1.44 −2.10 1415704_a_at 5010 4472 3850 3285 −1.12 −1.30 −1.52 1415707_at 1111 1317 1468 1535 1.19 1.32 1.38 1415714_a_at 4941 4632 2720 2379 −1.07 −1.82 −2.08 1415723_at 4272 3466 3385 3062 −1.23 −1.26 −1.40 1415733_a_at 13615 13963 9719 9991 1.03 −1.40 −1.36 1415735_at 2025 2617 3355 3642 1.29 1.66 1.80 1415736_at 4957 3953 2536 1805 −1.25 −1.95 −2.75 1415738_at 1914 1941 1575 1395 1.01 −1.22 −1.37 1415742_at 749 837 856 987 1.12 1.14 1.32 1415746_at 726 949 1075 1501 1.31 1.48 2.07 1415749_a_at 2368 2397 2111 1912 1.01 −1.12 −1.24 1415754_at 3512 3195 3099 2411 −1.10 −1.13 −1.46 1415755_a_at 2983 3602 3890 4068 1.21 1.30 1.36 1415756_a_at 3581 3290 2710 2706 −1.09 −1.32 −1.32 1415757_at 901 1073 1189 1337 1.19 1.32 1.48 1415764_at 3381 3218 2545 2419 −1.05 −1.33 −1.40 1415783_at 4869 4728 4237 3960 −1.03 −1.15 −1.23 1415788_at 1490 1572 1169 1046 1.05 −1.27 −1.42 1415791_at 2983 2870 2364 1805 −1.04 −1.26 −1.65 1415797_at 319 488 522 805 1.53 1.64 2.53 1415802_at 8566 8379 4763 4548 −1.02 −1.80 −1.88 1415812_at 31926 36029 41778 58920 1.13 1.31 1.85 1415814_at 1760 2239 1514 1433 1.27 −1.16 −1.23 1415816_at 5617 5279 4428 5553 −1.06 −1.27 −1.01 1415818_at 2554 2785 2838 3335 1.09 1.11 1.31 1415830_at 586 494 424 318 −1.19 −1.38 −1.84 1415834_at 579 703 419 430 1.21 −1.38 −1.35 1415840_at 1636 1461 974 856 −1.12 −1.68 −1.91 1415850_at 824 880 1129 1093 1.07 1.37 1.33 1415856_at 148 168 172 242 1.14 1.16 1.63 1415875_at 83 38 34 51 −2.19 −2.43 −1.63 1415876_a_at 13888 14344 16149 18965 1.03 1.16 1.37 1415879_a_at 33385 37008 41034 49898 1.11 1.23 1.49 1415882_at 20588 18774 17207 17741 −1.10 −1.20 −1.16 1415886_at 637 966 1017 1132 1.51 1.60 1.78 1415901_at 1435 1699 1682 1903 1.18 1.17 1.33 1415907_at 1656 1817 2329 2446 1.10 1.41 1.48 1415909_at 1788 1949 1414 1451 1.09 −1.26 −1.23 1415915_at 2843 3059 3559 3668 1.08 1.25 1.29 1415930_a_at 14546 13685 14019 11677 −1.06 −1.04 −1.25 1415935_at 1687 1988 2011 2446 1.18 1.19 1.45 1415947_at 7499 6219 8373 7163 −1.21 1.12 −1.05 1415951_at 496 588 587 717 1.19 1.18 1.45 1415961_at 2152 2177 2503 3192 1.01 1.16 1.48 1415966_a_at 29789 33932 35207 35979 1.14 1.18 1.21 1415971_at 1825 1273 1649 1440 −1.43 −1.11 −1.27 1415974_at 1694 2075 2211 2392 1.22 1.31 1.41 1415977_at 444 603 658 715 1.36 1.48 1.61 1415987_at 8838 9568 10218 11109 1.08 1.16 1.26 1415990_at 27024 32941 29714 35847 1.22 1.10 1.33 1415991_a_at 3051 3384 4293 4892 1.11 1.41 1.60 1415996_at 10650 22628 23188 27989 2.12 2.18 2.63 1415998_at 33371 40497 35239 46095 1.21 1.06 1.38 1416013_at 926 1171 1314 1772 1.26 1.42 1.91 1416014_at 1518 981 801 662 −1.55 −1.90 −2.29 1416016_at 232 236 387 358 1.02 1.67 1.55 1416019_at 336 291 275 269 −1.15 −1.22 −1.25 1416027_at 2414 2298 1834 1569 −1.05 −1.32 −1.54 1416032_at 1053 1425 1776 1638 1.35 1.69 1.56 1416046_a_at 4982 5500 3916 3426 1.10 −1.27 −1.45 1416048_at 1089 1174 1589 1635 1.08 1.46 1.50 1416050_a_at 903 1023 1209 1283 1.13 1.34 1.42 1416051_at 128 165 178 252 1.28 1.39 1.97 1416061_at 1318 1255 1052 964 −1.05 −1.25 −1.37 1416064_a_at 12341 12004 9273 10433 −1.03 −1.33 −1.18 1416069_at 1055 1396 1197 1313 1.32 1.13 1.24 1416079_a_at 1323 1494 1456 1611 1.13 1.10 1.22 1416082_at 13983 13415 11321 10270 −1.04 −1.24 −1.36 1416091_at 1996 2372 2622 3315 1.19 1.31 1.66 1416106_at 1108 939 1035 775 −1.18 −1.07 −1.43 1416111_at 368 212 288 138 −1.74 −1.28 −2.68 1416112_at 7587 9334 8583 12194 1.23 1.13 1.61 1416113_at 1810 1965 2224 2559 1.09 1.23 1.41 1416125_at 550 764 772 809 1.39 1.40 1.47 1416129_at 1270 1118 1078 734 −1.14 −1.18 −1.73 1416140_a_at 1672 1904 1977 1952 1.14 1.18 1.17 1416142_at 614 690 511 333 1.12 −1.20 −1.85 1416155_at 3723 3890 2824 2551 1.04 −1.32 −1.46 1416175_a_at 21409 19416 15845 13003 −1.10 −1.35 −1.65 1416176_at 2064 1801 1869 1358 −1.15 −1.10 −1.52 1416177_at 884 734 669 666 −1.20 −1.32 −1.33 1416181_at 1982 1958 1504 1705 −1.01 −1.32 −1.16 1416183_a_at 40384 48786 54318 64528 1.21 1.35 1.60 1416185_a_at 4447 4224 3331 2724 −1.05 −1.33 −1.63 1416186_at 404 340 342 213 −1.19 −1.18 −1.90 1416195_at 1575 1576 1933 2022 1.00 1.23 1.28 1416209_at 3673 4359 4108 4135 1.19 1.12 1.13 1416210_at 2605 2387 2225 2041 −1.09 −1.17 −1.28 1416223_at 629 633 838 882 1.01 1.33 1.40 1416226_at 1514 1558 2186 2127 1.03 1.44 1.40 1416238_at 982 1045 1322 1446 1.06 1.35 1.47 1416240_at 22627 18896 18958 17768 −1.20 −1.19 −1.27 1416252_at 1031 1322 1235 1464 1.28 1.20 1.42 1416254_a_at 432 478 497 673 1.11 1.15 1.56 1416256_a_at 4550 5806 4704 5339 1.28 1.03 1.17 1416259_at 573 393 417 336 −1.46 −1.37 −1.71 1416261_at 328 394 350 470 1.20 1.07 1.43 1416268_at 4666 4083 4613 3784 −1.14 −1.01 −1.23 1416271_at 3787 4661 4246 5035 1.23 1.12 1.33 1416272_at 4874 4932 3921 3693 1.01 −1.24 −1.32 1416280_at 1640 1595 1340 1270 −1.03 −1.22 −1.29 1416283_at 1026 1225 1415 1355 1.19 1.38 1.32 1416284_at 5006 5498 6000 6739 1.10 1.20 1.35 1416292_at 13464 12624 11145 11453 −1.07 −1.21 −1.18 1416294_at 1274 1556 1654 2003 1.22 1.30 1.57 1416300_a_at 81172 93900 86598 106206 1.16 1.07 1.31 1416312_at 1570 1597 1351 1503 1.02 −1.16 −1.04 1416315_at 1812 2063 2221 2496 1.14 1.23 1.38 1416326_at 8540 9522 10268 12292 1.11 1.20 1.44 1416329_at 1231 933 1064 976 −1.32 −1.16 −1.26 1416331_a_at 4998 5244 6828 7398 1.05 1.37 1.48 1416339_a_at 1730 1851 1929 2312 1.07 1.12 1.34 1416340_a_at 1678 1836 2208 2386 1.09 1.32 1.42 1416350_at 209 134 177 85 −1.56 −1.18 −2.46 1416366_at 27546 25654 21110 19836 −1.07 −1.30 −1.39 1416368_at 3559 3865 3913 4425 1.09 1.10 1.24 1416369_at 728 542 558 430 −1.34 −1.30 −1.69 1416371_at 934 773 973 1314 −1.21 1.04 1.41 1416384_a_at 3771 3990 4230 4569 1.06 1.12 1.21 1416393_at 5020 5227 4128 2942 1.04 −1.22 −1.71 1416405_at 5254 5912 7260 10205 1.13 1.38 1.94 1416411_at 3752 3573 3504 3347 −1.05 −1.07 −1.12 1416412_at 716 471 369 274 −1.52 −1.94 −2.61 1416414_at 461 561 703 739 1.22 1.52 1.60 1416417_a_at 29794 33340 35044 38096 1.12 1.18 1.28 1416424_at 3969 4305 4914 5377 1.08 1.24 1.35 1416425_at 3908 4090 4560 4505 1.05 1.17 1.15 1416427_at 14038 14608 14480 17881 1.04 1.03 1.27 1416436_a_at 3463 3513 2761 2608 1.01 −1.25 −1.33 1416438_at 1704 1946 2041 2300 1.14 1.20 1.35 1416452_at 5918 6059 6368 7090 1.02 1.08 1.20 1416455_a_at 49845 53641 55445 64019 1.08 1.11 1.28 1416457_at 1208 1356 1592 1930 1.12 1.32 1.60 1416462_at 3796 3321 2539 2621 −1.14 −1.49 −1.45 1416478_a_at 49370 54196 49980 56965 1.10 1.01 1.15 1416479_a_at 3314 4024 3824 5065 1.21 1.15 1.53 1416494_at 24034 24945 28712 32059 1.04 1.19 1.33 1416496_at 9192 10747 9867 10827 1.17 1.07 1.18 1416498_at 1234 1020 1151 968 −1.21 −1.07 −1.28 1416502_a_at 1327 1624 1659 1918 1.22 1.25 1.45 1416506_at 5718 5208 4876 4228 −1.10 −1.17 −1.35 1416510_at 5555 6339 5912 6679 1.14 1.06 1.20 1416513_at 1582 2144 2762 2762 1.35 1.75 1.75 1416514_a_at 888 805 648 439 −1.10 −1.37 −2.02 1416517_at 411 441 486 580 1.07 1.18 1.41 1416524_at 4034 4167 4527 5256 1.03 1.12 1.30 1416540_at 1017 1340 1386 1769 1.32 1.36 1.74 1416547_at 12925 12431 11457 10620 −1.04 −1.13 −1.22 1416555_at 2837 2868 2221 2008 1.01 −1.28 −1.41 1416563_at 1374 1532 1043 788 1.11 −1.32 −1.74 1416576_at 230 236 432 441 1.02 1.88 1.92 1416587_a_at 372 605 623 822 1.63 1.68 2.21 1416595_at 1722 1750 1272 1269 1.02 −1.35 −1.36 1416604_at 55121 62820 59589 71198 1.14 1.08 1.29 1416612_at 424 520 635 826 1.23 1.50 1.95 1416621_at 869 1007 1063 1287 1.16 1.22 1.48 1416629_at 412 524 548 620 1.27 1.33 1.50 1416634_at 3167 2719 1899 1420 −1.16 −1.67 −2.23 1416635_at 4444 3643 3384 2684 −1.22 −1.31 −1.66 1416637_at 525 603 661 780 1.15 1.26 1.49 1416647_at 5775 6096 7099 7557 1.06 1.23 1.31 1416648_at 2599 3174 3890 4330 1.22 1.50 1.67 1416656_at 1412 1659 1596 1864 1.18 1.13 1.32 1416668_at 10958 10417 8267 7237 −1.05 −1.33 −1.51 1416680_at 2599 1810 1455 813 −1.44 −1.79 −3.20 1416683_at 1687 2209 2493 2585 1.31 1.48 1.53 1416690_at 1379 1680 1929 1834 1.22 1.40 1.33 1416699_at 6446 6175 4968 5208 −1.04 −1.30 −1.24 1416703_at 2541 2311 2251 1680 −1.10 −1.13 −1.51 1416706_at 408 412 258 254 1.01 −1.58 −1.61 1416708_a_at 807 815 975 1044 1.01 1.21 1.29 1416709_a_at 1287 1148 920 920 −1.12 −1.40 −1.40 1416713_at 920 1162 1424 2002 1.26 1.55 2.18 1416730_at 436 492 540 650 1.13 1.24 1.49 1416731_at 1678 1349 1389 1118 −1.24 −1.21 −1.50 1416737_at 1600 2387 2293 2936 1.49 1.43 1.84 1416740_at 1068 1202 1516 1606 1.13 1.42 1.50 1416749_at 4558 5528 3766 3810 1.21 −1.21 −1.20 1416752_at 18842 22289 23077 26541 1.18 1.22 1.41 1416755_at 1571 1157 1295 897 −1.36 −1.21 −1.75 1416766_at 2214 2261 2504 2834 1.02 1.13 1.28 1416791_a_at 1176 1162 1174 1630 −1.01 −1.00 1.39 1416805_at 1361 1327 1132 959 −1.03 −1.20 −1.42 1416808_at 2839 2486 1876 1518 −1.14 −1.51 −1.87 1416819_at 7318 8511 7739 8109 1.16 1.06 1.11 1416824_at 6820 5799 4916 4447 −1.18 −1.39 −1.53 1416832_at 179 250 238 315 1.40 1.33 1.76 1416836_at 2043 2339 2345 2519 1.15 1.15 1.23 1416841_at 761 651 582 494 −1.17 −1.31 −1.54 1416842_at 5799 5337 5053 4625 −1.09 −1.15 −1.25 1416845_at 253 365 392 412 1.44 1.55 1.63 1416867_at 539 510 644 503 −1.06 1.19 −1.07 1416883_at 3457 4227 5144 5330 1.22 1.49 1.54 1416884_at 1755 1451 1259 1064 −1.21 −1.39 −1.65 1416896_at 354 336 521 404 −1.05 1.47 1.14 1416903_at 2268 2513 2807 2977 1.11 1.24 1.31 1416912_at 2816 2469 2287 1840 −1.14 −1.23 −1.53 1416928_at 295 289 197 136 −1.02 −1.50 −2.16 1416931_at 695 726 597 533 1.05 −1.16 −1.30 1416933_at 1482 1837 2077 2466 1.24 1.40 1.66 1416940_at 9984 10810 10055 11650 1.08 1.01 1.17 1416943_at 1721 1477 1227 872 −1.16 −1.40 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317 −1.23 −1.62 −1.98 1455307_at 487 544 697 794 1.12 1.43 1.63 1455309_at 761 829 1263 1387 1.09 1.66 1.82 1455312_at 785 972 944 1067 1.24 1.20 1.36 1455320_at 3658 2918 2870 2793 −1.25 −1.27 −1.31 1455340_at 576 384 329 275 −1.50 −1.75 −2.09 1455349_at 697 526 549 463 −1.32 −1.27 −1.50 1455353_at 968 809 836 782 −1.20 −1.16 −1.24 1455356_at 320 299 499 662 −1.07 1.56 2.07 1455387_at 1358 1115 995 758 −1.22 −1.36 −1.79 1455390_at 1575 1427 1439 1118 −1.10 −1.09 −1.41 1455434_a_at 6402 5782 5247 4407 −1.11 −1.22 −1.45 1455442_at 74 104 176 197 1.41 2.37 2.67 1455450_at 1232 1200 1327 1592 −1.03 1.08 1.29 1455456_a_at 1242 1516 1332 1587 1.22 1.07 1.28 1455462_at 218 251 334 356 1.15 1.53 1.63 1455479_a_at 12338 12135 7678 6396 −1.02 −1.61 −1.93 1455482_at 516 724 797 1018 1.40 1.54 1.97 1455491_at 1099 1208 811 846 1.10 −1.36 −1.30 1455506_at 5998 5890 8637 9404 −1.02 1.44 1.57 1455508_at 354 367 312 217 1.04 −1.14 −1.63 1455538_at 942 726 609 472 −1.30 −1.55 −2.00 1455585_at 601 526 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1.33 1.19 1.43 1455944_at 153 127 219 289 −1.21 1.43 1.88 1455945_at 192 166 136 117 −1.16 −1.41 −1.65 1456046_at 3587 3017 2786 2266 −1.19 −1.29 −1.58 1456058_at 807 745 690 598 −1.08 −1.17 −1.35 1456059_at 4664 4475 3594 3214 −1.04 −1.30 −1.45 1456061_at 740 574 371 258 −1.29 −1.99 −2.87 1456065_at 128 49 171 119 −2.60 1.33 −1.07 1456092_at 86 52 58 26 −1.67 −1.49 −3.35 1456099_at 128 174 254 207 1.35 1.98 1.61 1456161_at 403 283 297 279 −1.42 −1.36 −1.44 1456169_at 128 171 178 144 1.34 1.39 1.13 1456210_at 150 178 101 68 1.18 −1.48 −2.21 1456241_a_at 3667 3705 4635 4984 1.01 1.26 1.36 1456257_at 495 565 327 409 1.14 −1.51 −1.21 1456315_a_at 5639 5549 3253 2716 −1.02 −1.73 −2.08 1456398_at 1951 1675 1544 1204 −1.16 −1.26 −1.62 1456487_at 270 438 425 592 1.62 1.57 2.19 1456599_at 106 165 118 109 1.55 1.11 1.03 1456604_a_at 2365 2051 1676 1367 −1.15 −1.41 −1.73 1456611_at 462 581 505 608 1.26 1.09 1.31 1456625_at 192 140 145 126 −1.37 −1.33 −1.52 1456643_at 386 308 278 233 −1.25 −1.39 −1.65 1456659_at 319 363 307 153 1.14 −1.04 −2.08 1456727_a_at 2775 2975 4693 5107 1.07 1.69 1.84 1456768_a_at 1333 1602 1733 2588 1.20 1.30 1.94 1456774_at 324 594 806 961 1.83 2.49 2.97 1456777_at 38 14 75 13 −2.79 1.95 −3.02 1456827_at 196 148 119 61 −1.33 −1.64 −3.22 1456836_at 151 39 112 115 −3.85 −1.34 −1.31 1456871_a_at 1810 1658 2405 2210 −1.09 1.33 1.22 1456888_at 252 244 313 371 −1.03 1.24 1.47 1456896_at 473 464 642 654 −1.02 1.36 1.38 1456914_at 239 197 190 142 −1.21 −1.26 −1.69 1457058_at 245 319 349 556 1.31 1.43 2.27 1457111_at 267 251 189 227 −1.07 −1.41 −1.18 1457276_at 149 225 240 200 1.51 1.61 1.35 1457285_at 1194 1178 764 664 −1.01 −1.56 −1.80 1457334_at 286 516 618 643 1.80 2.16 2.25 1457401_at 63 89 114 167 1.41 1.81 2.64 1457448_at 154 79 90 117 −1.94 −1.71 −1.32 1457501_at 20 78 111 63 3.99 5.68 3.23 1457508_at 400 281 286 239 −1.42 −1.40 −1.67 1457557_at 81 31 72 23 −2.59 −1.13 −3.55 1457626_at 58 84 135 152 1.44 2.31 2.59 1457671_at 767 700 555 483 −1.10 −1.38 −1.59 1457681_at 1108 992 1385 1651 −1.12 1.25 1.49 1457707_at 55 71 153 177 1.29 2.78 3.21 1457745_at 361 391 519 505 1.08 1.44 1.40 1457747_at 8 14 30 35 1.77 3.81 4.34 1457801_at 268 388 343 329 1.45 1.28 1.23 1458058_at 149 104 122 59 −1.44 −1.21 −2.53 1458190_at 120 146 291 240 1.21 2.41 2.00 1458311_at 249 304 433 381 1.22 1.74 1.53 1458353_at 162 269 340 244 1.66 2.10 1.51 1458438_at 240 181 180 118 −1.33 −1.34 −2.03 1458455_at 566 438 512 358 −1.29 −1.11 −1.58 1458461_at 12 21 40 20 1.66 3.22 1.57 1458478_at 65 48 12 53 −1.36 −5.63 −1.23 1458482_at 1340 1453 1156 1017 1.08 −1.16 −1.32 1458624_at 1590 1831 2206 2675 1.15 1.39 1.68 1458780_at 20 68 74 55 3.33 3.61 2.70 1458863_at 152 101 37 85 −1.50 −4.15 −1.79 1459108_a_at 219 259 328 445 1.18 1.50 2.03 1459220_at 138 217 222 276 1.57 1.61 2.00 1459363_at 312 405 407 506 1.30 1.31 1.62 1459578_at 54 61 155 88 1.12 2.85 1.62 1460033_at 74 180 125 105 2.42 1.69 1.42 1460053_at 242 144 218 221 −1.68 −1.11 −1.10 1460113_at 104 187 144 134 1.80 1.38 1.29 1460165_at 9064 9043 7129 6522 −1.00 −1.27 −1.39 1460167_at 988 1120 1063 1253 1.13 1.08 1.27 1460169_a_at 2453 3136 3555 4351 1.28 1.45 1.77 1460177_at 1301 1575 1640 1671 1.21 1.26 1.28 1460184_at 36182 38955 42606 49147 1.08 1.18 1.36 1460189_at 4600 3988 3323 2755 −1.15 −1.38 −1.67 1460194_at 12145 13386 14000 14613 1.10 1.15 1.20 1460196_at 1079 1068 1158 1385 −1.01 1.07 1.28 1460210_at 683 848 775 1026 1.24 1.13 1.50 1460214_at 27 97 92 108 3.67 3.46 4.07 1460216_at 5275 5712 6310 7377 1.08 1.20 1.40 1460230_at 106 114 120 192 1.07 1.13 1.81 1460239_at 3477 3308 3484 3037 −1.05 1.00 −1.15 1460251_at 464 467 407 262 1.01 −1.14 −1.77 1460254_at 1563 1408 1168 924 −1.11 −1.34 −1.69 1460271_at 157 66 118 125 −2.38 −1.33 −1.26 1460276_a_at 822 886 967 1097 1.08 1.18 1.33 1460321_at 129 52 117 105 −2.48 −1.10 −1.23 1460326_at 1395 1325 1867 1690 −1.05 1.34 1.21 1460328_at 619 628 880 862 1.01 1.42 1.39 1460329_at 713 637 458 504 −1.12 −1.56 −1.42 1460330_at 1601 1521 1413 1219 −1.05 −1.13 −1.31 1460331_at 5861 5156 4527 4030 −1.14 −1.29 −1.45 1460336_at 2689 2686 4293 5218 −1.00 1.60 1.94 1460337_at 4383 5948 3663 4114 1.36 −1.20 −1.07 1460344_at 1002 1085 1313 1398 1.08 1.31 1.40 1460396_at 483 621 790 817 1.29 1.63 1.69 1460409_at 1345 1292 1713 2001 −1.04 1.27 1.49 1460412_at 58 20 45 57 −2.84 −1.30 −1.03 1460420_a_at 634 820 934 1142 1.29 1.47 1.80 1460428_at 919 958 1120 1123 1.04 1.22 1.22 1460432_a_at 12140 9937 10609 8730 −1.22 −1.14 −1.39 1460433_at 662 763 813 1034 1.15 1.23 1.56 1460435_at 573 713 699 935 1.25 1.22 1.63 1460444_at 329 323 411 491 −1.02 1.25 1.49 1460500_at 313 176 158 98 −1.78 −1.98 −3.20 1460510_a_at 3505 3184 2702 2908 −1.10 −1.30 −1.21 1460539_at 68 139 141 153 2.04 2.07 2.25 1460547_a_at 4912 3450 2670 1733 −1.42 −1.84 −2.84 1460552_at 2039 2109 2286 2886 1.03 1.12 1.42 1460557_at 1577 1866 1401 1297 1.18 −1.13 −1.22 1460559_at 2459 2747 3020 4193 1.12 1.23 1.71 1460570_at 90 123 168 176 1.36 1.87 1.95 1460573_at 838 611 460 341 −1.37 −1.82 −2.46 1460576_at 1390 1299 1107 878 −1.07 −1.26 −1.58 1460580_at 950 1086 1029 1226 1.14 1.08 1.29 1460586_at 802 890 990 1316 1.11 1.23 1.64 1460603_at 703 632 490 590 −1.11 −1.43 −1.19 1460607_at 43 102 138 99 2.38 3.21 2.30 1460610_at 191 208 233 328 1.09 1.22 1.72 1460614_at 331 289 291 199 −1.14 −1.14 −1.66 1460624_at 363 266 217 198 −1.36 −1.67 −1.83 1460643_at 270 360 304 400 1.34 1.13 1.48 1460644_at 2028 2060 2523 2936 1.02 1.24 1.45 1460645_at 1384 1178 880 926 −1.17 −1.57 −1.49 1460648_at 1100 1245 1478 1574 1.13 1.34 1.43 1460674_at 477 623 657 970 1.31 1.38 2.04 1460675_at 412 429 642 729 1.04 1.56 1.77 1460695_a_at 2491 2664 2132 1926 1.07 −1.17 −1.29 1460704_at 664 756 815 930 1.14 1.23 1.40 1460716_a_at 2287 2216 2090 1679 −1.03 −1.09 −1.36 1460720_at 1749 2092 2554 2716 1.20 1.46 1.55 1460732_a_at 495 527 571 770 1.06 1.15 1.56 AFFX−b−ActinMur 37967 41791 48255 54572 1.10 1.27 1.44 M12481_3_at 37967 41791 48255 54572 1.10 1.27 1.44 AFFX−GapdhMur 90974 104691 98912 122441 1.15 1.09 1.35 M32599_M_at 90974 104691 98912 122441 1.15 1.09 1.35 Probe Set ID Treatment Entrez Info 1415670_at Lgx only Copg 1415671_at Res & Lgx Atp6v0d1 1415672_at Res & Lgx Golga7 1415677_at Res & Lgx Dhrs1 1415679_at Lgx only Psenen 1415684_at Lgx only Atg5 1415696_at Res only Sar1a 1415700_a_at Res & Lgx Ssr3 1415704_a_at Lgx only Cdv3 1415707_at Lgx only Anapc2 1415714_a_at Res & Lgx 2610209M04Rik 1415723_at Res & Lgx Eif5 1415733_a_at Lgx only 1110019J04Rik 1415735_at Lgx only Ddb1 1415736_at Res & Lgx Pfdn5 1415738_at Res & Lgx Txndc12 1415742_at Lgx only Aup1 1415746_at Lgx only Cic 1415749_a_at Lgx only Rragc 1415754_at Lgx only Polr2f 1415755_a_at Lgx only Ube2v1 1415756_a_at Res & Lgx Snapap 1415757_at Lgx only Gbf1 1415764_at Lgx only Zc3h11a 1415783_at Lgx only Vps35 1415788_at Lgx only Ublcp1 1415791_at Res & Lgx Rnf34 1415797_at Lgx only Ddr1 1415802_at Res & Lgx Slc16a1 1415812_at Lgx only Gsn 1415814_at CR only Atp6v1b2 1415816_at Res only Cct7 1415818_at Lgx only Anxav6 1415830_at Lgx only Orc5l 1415834_at Res only Dusp6 1415840_at Res & Lgx Elovl5 1415850_at Res & Lgx Rasa3 1415856_at Lgx only Emb 1415875_at Res only 3010003L21Rik 1415876_a_at Lgx only Rps26 1415879_a_at Lgx only Rplp2 1415882_at Res only Ghitm 1415886_at All Sh2d3c 1415901_at Lgx only Plod3 1415907_at Lgx only Ccnd3 1415909_at Res & Lgx Stip1 1415915_at Res & Lgx Ddx1 1415930_a_at Lgx only Map1lc3b 1415935_at Res & Lgx Smoc2 1415947_at CR only Creg1 1415951_at Lgx only Fkbp10 1415961_at Lgx only Itm2c 1415966_a_at Lgx only Ndufv1 1415971_at CR only Marcks 1415974_at Lgx only Map2k2 1415977_at Lgx only Isyna1 1415987_at Lgx only Hdlbp 1415990_at CR & Lgx Vdac2 1415991_a_at Res & Lgx Klhdc3 1415996_at All Txnip 1415998_at Lgx only Vdac1 1416013_at Res & Lgx Pld3 1416014_at All Abce1 1416016_at Res & Lgx Tap1 1416019_at Res only Dr1 1416027_at Res & Lgx Pdcd6 1416032_at Lgx only Tmem109 1416046_a_at Lgx only Fuca2 1416048_at Res & Lgx Phc2 1416050_a_at Lgx only Scarb1 1416051_at Lgx only C2 1416061_at Lgx only Tbc1d15 1416064_a_at Res only Hspa5 1416069_at CR only Pfkp 1416079_a_at Lgx only Arpc1a 1416082_at Res & Lgx Rab1 1416091_at Lgx only Mtap4 1416106_at Lgx only Kti12 1416111_at CR & Lgx Cd83 1416112_at Lgx only Cox8a 1416113_at Lgx only Fkbp8 1416125_at Lgx only Fkbp5 1416129_at Lgx only Errfi1 1416140_a_at Lgx only Dhx30 1416142_at Lgx only Rps6 1416155_at Res & Lgx Hmgb3 1416175_a_at Res & Lgx Vdac3 1416176_at Lgx only Hmgb1 1416177_at Res & Lgx Rbmxrt 1416181_at Res only Mesdc2 1416183_a_at Lgx only Ldhb 1416185_a_at Lgx only Adh5 1416186_at Lgx only Pnrc2 1416195_at Lgx only RP23−136K12.4 1416209_at CR & Lgx Glud1 1416210_at Lgx only Imp3 1416223_at Lgx only Sh3bp5l 1416226_at Lgx only Arpc1b 1416238_at Lgx only Tie1 1416240_at Lgx only Psmb7 1416252_at Lgx only Stk38 1416254_a_at Lgx only Vps16 1416256_a_at CR only Tubb5 1416259_at CR & Lgx Pex12 1416261_at Lgx only Tmem19 1416268_at Lgx only Ets2 1416271_at CR & Lgx Perp 1416272_at Lgx only Map2k1ip1 1416280_at Lgx only Sae2 1416283_at Res & Lgx Gart 1416284_at Lgx only Mrpl28 1416292_at Res & Lgx Prdx3 1416294_at Lgx only Scamp3 1416300_a_at Lgx only Slc25a3 1416312_at Res only Rars 1416315_at Lgx only Abhd4 1416326_at Lgx only Crip1 1416329_at CR only Cyfip1 1416331_a_at Lgx only Nfe2l1 1416339_a_at Lgx only Prkcsh 1416340_a_at Lgx only Man2b1 1416350_at Lgx only Klf16 1416366_at Lgx only Ndufc2 1416368_at Lgx only Gsta4 1416369_at Lgx only Hiatl1 1416371_at Lgx only Apod 1416384_a_at Lgx only Cope 1416393_at Lgx only Emg1 1416405_at Lgx only Bgn 1416411_at Lgx only Gstm2 1416412_at Res & Lgx Nsmaf 1416414_at Lgx only Emilin1 1416417_a_at Lgx only Ndufb7 1416424_at Lgx only M6prbp1 1416425_at Lgx only Pex19 1416427_at Lgx only Ccni 1416436_a_at Res & Lgx Uqcc 1416438_at Lgx only Puf60 1416452_at Lgx only Oat 1416455_a_at Lgx only Cryab 1416457_at Lgx only Ddah2 1416462_at Res & Lgx Caprin1 1416478_a_at Lgx only Mdh2 1416479_a_at Lgx only Tmem14c 1416494_at Lgx only Ndufs5 1416496_at CR & Lgx Mrfap1 1416498_at CR & Lgx Ppic 1416502_a_at Res & Lgx Preb 1416506_at Lgx only Psma6 1416510_at Lgx only Mrpl4 1416513_at Lgx only Lamb2 1416514_a_at Lgx only Fscn1 1416517_at Lgx only Pnpla6 1416524_at Lgx only Spop 1416540_at Lgx only Hgs 1416547_at Lgx only Ndufb3 1416555_at Res & Lgx Ei24 1416563_at Lgx only Ctps 1416576_at Lgx only Socs3 1416587_a_at Res & Lgx Xrcc1 1416595_at Lgx only Mrps22 1416604_at Lgx only Cyc1 1416612_at Lgx only Cyp1b1 1416621_at Res & Lgx Llgl1 1416629_at Lgx only Slc1a5 1416634_at Res & Lgx 5730536A07Rik 1416635_at Res & Lgx Smpdl3a 1416637_at Lgx only Slc4a2 1416647_at Lgx only Bckdha 1416648_at Lgx only Dync1h1 1416656_at Lgx only Clic1 1416668_at Lgx only Ttc35 1416680_at Res & Lgx Ube3a 1416683_at Lgx only Plxnb2 1416690_at Res & Lgx Gtpbp2 1416699_at Res only 1110008F13Rik 1416703_at Lgx only Mapk14 1416706_at Res only Rpe 1416708_a_at Lgx only Gramd1a 1416709_a_at Res & Lgx Ngrn 1416713_at Lgx only Tppp3 1416730_at Lgx only Rcl1 1416731_at Lgx only Top2b 1416737_at Lgx only Gys1 1416740_at Lgx only Col5a1 1416749_at CR only Htra1 1416752_at Lgx only Ldb3 1416755_at CR & Lgx Dnajb1 1416766_at Lgx only Mosc2 1416791_a_at Lgx only Nxf1 1416805_at Lgx only 1110032E23Rik 1416808_at Res & Lgx Nid1 1416819_at CR only Cdc37 1416824_at Res & Lgx B230118H07Rik 1416832_at Lgx only Slc39a8 1416836_at Lgx only Lrp10 1416841_at Lgx only 1110059E24Rik 1416842_at Lgx only Gstm5 1416845_at Res & Lgx Tmem132a 1416867_at Res only Bet1 1416883_at Res & Lgx Clptm1 1416884_at Lgx only Cbx3 1416896_at Res only Rps6ka1 1416903_at Lgx only Nucb1 1416912_at Lgx only 6330407G11Rik 1416928_at Res & Lgx Rbm12 1416931_at Lgx only Nif3l1 1416933_at Res & Lgx Por 1416940_at Lgx only Ppif 1416943_at Lgx only Ube2e1 1416953_at CR only Ctgf 1416963_at Res only Ubac1 1416981_at Lgx only Foxo1 1416990_at Lgx only Rxrb 1417000_at Lgx only Abtb1 1417006_at Lgx only Commd4 1417007_a_at Lgx only Vps4b 1417008_at Lgx only Crat 1417010_at Lgx only Zfp238 1417018_at Lgx only Efemp2 1417026_at Lgx only Pfdn1 1417044_at Lgx only Lcmt1 1417049_at CR only Rhd 1417061_at All Slc40a1 1417065_at CR only Egr1 1417068_a_at Res & Lgx Ptpn1 1417073_a_at Lgx only Qk 1417075_at Lgx only 2010309E21Rik 1417081_a_at Lgx only Syngr2 1417082_at Lgx only Anp32b 1417091_at Lgx only Chuk 1417105_at Lgx only Trappc2l 1417109_at Res & Lgx Tinagl 1417112_at Res & Lgx Arl2bp 1417124_at Lgx only Dstn 1417127_at Lgx only Msx1 1417142_at Res & Lgx 4932442K08Rik 1417146_at Res & Lgx 2410018C20Rik 1417165_at Lgx only Mbd2 1417168_a_at Lgx only Usp2 1417170_at Lgx only Lztfl1 1417174_at Res & Lgx 1810021J13Rik 1417177_at Lgx only Galk1 1417180_at Res & Lgx Pcsk7 1417185_at Lgx only Ly6a 1417190_at Lgx only Pbef1 1417191_at Lgx only Dnajb9 1417207_at Lgx only Dvl2 1417209_at Lgx only Sertad2 1417226_at Lgx only Fbxw4 1417228_at Lgx only Capn1 1417233_at Res & Lgx Chchd4 1417238_at Lgx only Ewsr1 1417239_at Lgx only Cetn3 1417240_at Res & Lgx Zyx 1417241_at Res & Lgx X83328 1417258_at Res & Lgx Cct5 1417271_a_at Lgx only Eng 1417273_at Res & Lgx Pdk4 1417285_a_at Lgx only Ndufa5 1417291_at Res & Lgx Tnfrsf1a 1417294_at Lgx only Akr7a5 1417297_at All Itpr3 1417304_at Lgx only Chrd 1417306_at Lgx only Tyk2 1417307_at Lgx only Dmd 1417308_at Lgx only Pkm2 1417311_at Lgx only Crip2 1417312_at Lgx only Dkk3 1417327_at Lgx only Cav2 1417334_at Lgx only Stk19 1417349_at Lgx only Pldn 1417357_at Lgx only Emd 1417367_at Lgx only Ppp2ca 1417369_at Lgx only Hsd17b4 1417373_a_at CR & Res Tuba4a 1417382_at CR & Res Entpd5 1417389_at Lgx only Gpc1 1417392_a_at Lgx only Slc7a7 1417394_at Lgx only Klf4 1417397_at Lgx only Slc9a1 1417398_at CR & Lgx Rras2 1417399_at Lgx only Gas6 1417402_at Lgx only 1190017O12Rik 1417409_at Lgx only Jun 1417423_at All Grina 1417433_at Res only Lypla2 1417437_at CR only Xrcc6 1417441_at Lgx only Dnajc12 1417446_at Res & Lgx Slc12a4 1417466_at Lgx only Rgs5 1417475_at Lgx only Atp13a1 1417476_at Lgx only Fbxw5 1417478_a_at Res & Lgx Ppp2r3c 1417490_at Lgx only Ctsb 1417493_at Lgx only Bmi1 1417494_a_at Lgx only Cp 1417503_at Lgx only Rfc2 1417507_at Res only Cyb561 1417516_at Res & Lgx Ddit3 1417533_a_at Res & Lgx Itgb5 1417536_at Lgx only Zmat2 1417544_a_at Lgx only Flot2 1417552_at Lgx only Fap 1417562_at Res & Lgx Eif4ebp1 1417564_at Lgx only Med7 1417574_at Lgx only Cxcl12 1417578_a_at Lgx only Gmppa 1417581_at Lgx only Dhodh 1417588_at CR only Galnt3 1417590_at Res & Lgx Cyp27a1 1417592_at Lgx only Frap1 1417606_a_at Lgx only Calr 1417611_at Lgx only Tmem37 1417614_at Lgx only Ckm 1417626_at Lgx only Pde4dip 1417629_at CR only Prodh 1417631_at Res only Mknk1 1417636_at Lgx only Slc6a9 1417637_a_at Lgx only Hmg20b 1417659_at Res & Lgx Vps29 1417664_a_at Lgx only Ndrg3 1417665_a_at Lgx only Cpsf1 1417669_at Lgx only Abhd12 1417673_at Res & Lgx Grb14 1417680_at Lgx only Kcna5 1417681_at Lgx only Nudt21 1417683_at Lgx only Diablo 1417693_a_at Lgx only Gab1 1417712_at Lgx only Eif2s2 1417715_a_at Lgx only Got2 1417722_at Lgx only Pgls 1417724_at Lgx only Thoc4 1417727_at Lgx only Sfrs9 1417728_at Lgx only Mbd3 1417730_at Res & Lgx Ext1 1417762_a_at Lgx only Rpl8 1417775_at Lgx only Rpo1−4 1417777_at Lgx only Ltb4dh 1417778_at Lgx only Zfp35 1417791_a_at Lgx only Zfml 1417807_at Lgx only 2700038N03Rik 1417814_at CR only Pla2g5 1417825_at Res & Lgx Esd 1417827_at Lgx only Ngly1 1417840_at Lgx only 1500031L02Rik 1417842_at CR only Caml 1417865_at Res only Tnfaip1 1417868_a_at Lgx only Ctsz 1417889_at Lgx only Apobec2 1417893_at Lgx only Sfxn3 1417912_at Lgx only Tmem93 1417916_a_at Lgx only Fxc1 1417928_at Lgx only Pdlim4 1417933_at Lgx only Igfbp6 1417936_at Res & Lgx Ccl9 1417951_at Res & Lgx Eno3 1417953_at Lgx only D6Wsu176e 1417963_at CR only Pltp 1417970_at Lgx only Atp5s 1417974_at Lgx only Kpna4 1417983_a_at Lgx only Ube2v2 1417985_at All Nrarp 1418000_a_at Lgx only Itm2b 1418004_a_at Lgx only Tmem176b 1418007_at Lgx only 1810007M14Rik 1418025_at Res & Lgx Bhlhb2 1418031_at Res & Lgx Myo9b 1418048_at Lgx only 1110059G10Rik 1418049_at Lgx only Ltbp3 1418058_at Lgx only Eltd1 1418085_at Lgx only Prkcz 1418090_at Lgx only Plvap 1418093_a_at Lgx only Egf 1418124_at Res & Lgx Tmem85 1418128_at Lgx only Adcy6 1418148_at Res & Lgx Abhd1 1418181_at Lgx only Ptp4a3 1418183_a_at Lgx only Pscd1 1418186_at Lgx only Gstt1 1418187_at Lgx only Ramp2 1418209_a_at Res & Lgx Pfn2 1418223_at Res & Lgx Sec11a 1418228_at Lgx only Nfu1 1418244_at Res & Lgx Nat5 1418261_at All Syk 1418275_a_at Lgx only Elf2 1418277_at Lgx only rp9 1418296_at Lgx only Fxyd5 1418302_at Res & Lgx Ppt2 1418306_at CR only Crybb1 1418308_at Lgx only Hus1 1418310_a_at CR only Rlbp1 1418325_at Res only Sephs2 1418327_at Lgx only 1110058L19Rik 1418328_at Lgx only Cpt1b 1418364_a_at Res & Lgx Ftl1 1418373_at Res & Lgx Pgam2 1418384_at Lgx only Apool 1418394_a_at All Cd97 1418395_at Res only Slc47a1 1418421_at Lgx only Bcl6b 1418427_at Lgx only Kif5b 1418433_at Lgx only Cab39 1418456_a_at Lgx only Cxcl14 1418461_at Lgx only Sh3d19 1418462_at Lgx only Exosc9 1418464_at Lgx only Matn4 1418467_at CR & Lgx Smarcd3 1418479_at CR & Lgx Vps54 1418483_a_at Lgx only Ggta1 1418495_at Res only Zc3h8 1418506_a_at Res only Prdx2 1418518_at Lgx only Furin 1418528_a_at Res & Lgx Dad1 1418530_at Lgx only Nup160 1418532_at Lgx only Fzd2 1418551_at Lgx only Mybpc3 1418560_at Lgx only Pdha1 1418563_at Res & Lgx Serbp1 1418578_at Lgx only Dgka 1418583_at Lgx only Hint3 1418584_at Lgx only Ccnh 1418589_a_at Res & Lgx Mlf1 1418593_at Lgx only Taf6 1418595_at Lgx only S3−12 1418604_at CR only Avpr1a 1418621_at Lgx only Rab2 1418640_at Lgx only Sirt1 1418644_a_at Res & Lgx Stk11 1418646_at Lgx only Gna−rs1 1418649_at Res & Lgx Egln3 1418658_at Lgx only 2410005O16Rik 1418659_at Lgx only Clock 1418665_at Res only Impa2 1418681_at Lgx only Alg13 1418700_at Res only Lias 1418703_at Res & Lgx Rbms1 1418714_at Lgx only Dusp8 1418726_a_at Lgx only Tnnt2 1418739_at CR only Sgk2 1418749_at Lgx only Psd3 1418759_at CR only Ptpn20 1418763_at Res only Nit2 1418773_at Lgx only Fads3 1418775_at Res & Lgx AI837181 1418782_at Lgx only Rxrg 1418817_at Lgx only Chmp1b 1418835_at Lgx only Phlda1 1418838_at Lgx only Abcd1 1418840_at Lgx only Pdcd4 1418846_at CR only Ap4m1 1418847_at Lgx only Arg2 1418861_at Res only Pias4 1418863_at Lgx only Gata4 1418869_a_at Lgx only Pus1 1418874_a_at Lgx only Psmd4 1418885_a_at Res & Lgx Idh3b 1418899_at Lgx only Ufm1 1418924_at Lgx only Rassf7 1418926_at Res & Lgx Zeb1 1418928_a_at Lgx only 2310038H17Rik 1418929_at Lgx only Ift57 1418933_at Res only Slc1a6 1418947_at CR only Nek3 1418952_at Res & Lgx Txlnb 1418967_a_at Lgx only St7 1418968_at Lgx only Rb1cc1 1418986_a_at Lgx only Uxt 1418987_at Res only Pla2g2d 1418988_at Res & Lgx Pex7 1418996_a_at Lgx only Lyrm5 1419013_at Res only Gpatch1 1419026_at Lgx only Daxx 1419037_at Lgx only Csnk2a1 1419062_at Lgx only Epb4.1l3 1419070_at CR only Cys1 1419072_at Lgx only Gstm7 1419074_at Lgx only Chac2 1419081_at Lgx only Atg10 1419109_at Res & Lgx Hrc 1419131_at CR only F13b 1419144_at Lgx only Cd163 1419158_a_at CR only Hars2 1419164_at Res & Lgx Zfp260 1419169_at Lgx only Mapk6 1419170_at Lgx only Tmem157 1419174_at Lgx only 2410004B18Rik 1419182_at Lgx only Svep1 1419186_a_at Res & Lgx St8sia4 1419214_at Res only Tnfrsf11a 1419238_at Lgx only Abca7 1419258_at Lgx only Tcea1 1419272_at Res only Myd88 1419292_at Lgx only Htra3 1419295_at Res only Creb3l1 1419297_at CR only H2−Oa 1419302_at Res & Lgx Heyl 1419333_at Lgx only 1110008J03Rik 1419352_at Lgx only l7Rn6 1419354_at Lgx only Klf7 1419358_at Lgx only Sorcs2 1419366_at Res & Lgx Zmat5 1419375_at Res & Lgx Wbp4 1419398_a_at Lgx only Reep5 1419415_a_at CR only Rarg 1419428_a_at Lgx only Gaa 1419429_at Res & Lgx Cntfr 1419452_at Lgx only Uchl5 1419455_at Lgx only Il10rb 1419470_at Res & Lgx Gnb4 1419477_at Res only Clec2d 1419484_a_at Lgx only Gbas 1419491_at Res only Defb1 1419495_at Lgx only Immp2l 1419499_at Lgx only Gpam 1419518_at All Tuba8 1419527_at Lgx only Comp 1419550_a_at Lgx only Stk39 1419569_a_at Res only Isg20 1419584_at Lgx only Ttc28 1419609_at CR only Ccr1 1419630_a_at CR & Lgx Trim11 1419631_at Res & Lgx Was 1419645_at Lgx only Cstf2 1419657_a_at CR & Lgx Slc25a36 1419660_at Lgx only 1600012F09Rik 1419687_at Lgx only Macrod1 1419736_a_at Res & Lgx Eif1ay 1419762_at Res & Lgx Ubd 1419787_a_at Lgx only Zfp628 1419824_a_at Res & Lgx A230062G08Rik 1419952_at Lgx only 1700023D09Rik 1420099_at CR only D13Ertd787e 1420123_at Res & Lgx Tcta 1420183_at Lgx only Lor 1420325_at Res only Cramp1l 1420329_at Lgx only 4930455C21Rik 1420339_at Res only LOC100047915 1420374_at Res & Lgx Foxj2 1420375_at Res & Lgx Kif3a 1420377_at Lgx only St8sia2 1420387_at Res & Lgx Mpv17 1420388_at Lgx only Prss12 1420405_at Lgx only Slco1a4 1420427_a_at CR only Dhx32 1420497_a_at Res only Cebpz 1420502_at Lgx only Sat1 1420507_a_at Res & Lgx 3110031B13Rik 1420513_at Res & Lgx Efcab2 1420580_at Res only 4930429B21Rik 1420617_at CR & Lgx Cpeb4 1420619_a_at Lgx only Aes 1420654_a_at Lgx only Gbe1 1420657_at CR & Lgx Ucp3 1420684_at Lgx only Acox3 1420693_at Lgx only Myom1 1420703_at Lgx only Csf2ra 1420707_a_at Res only Traip 1420711_a_at Res & Lgx Pxmp3 1420715_a_at Res only Pparg 1420727_a_at Lgx only Tmlhe 1420770_at Lgx only Klk1b24 1420812_at Res only Hdac7a 1420815_at Res & Lgx Gdi2 1420829_a_at Res & Lgx Ywhaq 1420850_at Lgx only Crnkl1 1420851_at Lgx only Pard6g 1420858_at Lgx only Pkia 1420886_a_at Res & Lgx Xbp1 1420890_at Res & Lgx Hccs 1420895_at Lgx only Tgfbr1 1420909_at Lgx only Vegfa 1420911_a_at Lgx only Mfge8 1420925_at Lgx only Tub 1420960_at Res only Fancg 1420965_a_at Lgx only Enc1 1420969_at Lgx only Btbd14b 1420981_a_at Lgx only Lmo4 1420990_at Res only Chd1 1420991_at Lgx only Ankrd1 1421019_at Lgx only 1700021F05Rik 1421025_at Lgx only Agpat1 1421027_a_at Res & Lgx Mef2c 1421042_at Res only Arhgef2 1421054_at Lgx only Xpo4 1421087_at CR & Lgx Per3 1421096_at Res & Lgx Trpc1 1421099_at Lgx only Bhlhb3 1421140_a_at Lgx only Foxp1 1421164_a_at Lgx only Arhgef1 1421174_at CR only Irf4 1421254_a_at Res & Lgx Sgcg 1421265_a_at Lgx only Rbm38 1421287_a_at Res & Lgx Pecam1 1421292_a_at Lgx only A730008L03Rik 1421301_at Res & Lgx Zic2 1421361_at Res only Grk1 1421373_at Lgx only Cox4i2 1421374_a_at Res & Lgx Fxyd1 1421425_a_at Lgx only Rcan2 1421444_at Res only Pgr 1421468_at Lgx only Kcnj3 1421530_a_at Lgx only Grm8 1421534_at Lgx only Dfna5h 1421541_a_at Lgx only Mef2b 1421654_a_at Lgx only Lmna 1421657_a_at Lgx only Sox17 1421712_at Res only Sele 1421729_a_at Res & Lgx Fert2 1421733_a_at Res & Lgx Tpst1 1421743_a_at Res & Lgx Pcbp2 1421750_a_at Lgx only Vbp1 1421797_a_at Lgx only Snx12 1421808_at Res only Defb5 1421810_at Lgx only Dgcr2 1421813_a_at Lgx only Psap 1421820_a_at Lgx only Nf2 1421826_at Lgx only Dll4 1421861_at Lgx only Clstn1 1421871_at Lgx only Sh3bgrl 1421872_at Lgx only Rab24 1421880_at Res only Mtmr1 1421887_a_at Lgx only Aplp2 1421894_a_at Lgx only Tpp2 1421900_at Lgx only Eif2ak1 1421910_at CR & Lgx Tcf20 1421929_at Res & Lgx Epha4 1421960_at Lgx only Adcy3 1421985_a_at Lgx only Eif4e2 1422063_a_at Res & Lgx Pex5 1422085_at Res only Tbx19 1422122_at Lgx only Fcer2a 1422157_a_at Res & Lgx Itgb1bp1 1422160_at Res & Lgx H2−T24 1422183_a_at Res & Lgx Adra1b 1422185_a_at Lgx only Cyb5r3 1422202_at All Thrb 1422250_at Res only Map3k2 1422253_at Res only Col10a1 1422273_at CR only Mmp1b 1422303_a_at Lgx only Tnfrsf18 1422325_at CR only Magea5 1422349_at Res only Ccr1l1 1422368_at CR only V1ra5 1422429_at Res & Lgx Rnf14 1422431_at Res & Lgx Magee1 1422442_at Res & Lgx Smu1 1422443_at CR only Xpnpep1 1422470_at CR & Lgx Bnip3 1422476_at Lgx only Ifi30 1422479_at CR only Acss2 1422505_at Res & Lgx Chrac1 1422514_at Lgx only Aebp1 1422521_at Lgx only Dctn1 1422536_at Lgx only Tnni3 1422559_at Res & Lgx Ube2n 1422562_at Lgx only Rrad 1422568_at Lgx only Ndel1 1422579_at Lgx only Hspe1 1422580_at Lgx only Myl4 1422589_at Lgx only Rab3a 1422594_at Res only 5730470L24Rik 1422597_at Lgx only Mmp15 1422598_at Lgx only Casq1 1422601_at Lgx only Serpinb9 1422622_at Lgx only Nos3 1422624_at Res & Lgx Rev1 1422631_at CR only Ahr 1422636_at Lgx only Dmtf1 1422647_at Lgx only Ring1 1422654_at Res & Lgx Sgca 1422656_at Lgx only Rasl2−9 1422669_at Res & Lgx Ebag9 1422678_at Lgx only Dgat2 1422687_at Res only Nras 1422704_at Lgx only Gyk 1422710_a_at Lgx only Cacna1h 1422731_at Lgx only Limd1 1422750_a_at Lgx only Zmynd10 1422754_at Lgx only Tmod1 1422759_a_at Lgx only Xpo6 1422771_at Lgx only Smad6 1422794_at Lgx only Cul3 1422797_at Lgx only Mapbpip 1422799_at Lgx only Bat2 1422801_at Lgx only G3bp1 1422811_at Lgx only Slc27a1 1422819_at Lgx only Mrpl36 1422820_at Res & Lgx Lipe 1422845_at Res & Lgx Canx 1422855_at Lgx only Cpsf3 1422858_at Res & Lgx Trip4 1422869_at CR only Mertk 1422880_at Res only Sypl 1422884_at Res & Lgx Snrpd3 1422888_at Res & Lgx Rnf5 1422895_at Lgx only Vamp4 1422904_at Lgx only Fmo2 1422919_at Lgx only Hrasls 1422927_at Lgx only Yipf7 1422975_at Lgx only Mme 1423025_a_at Res & Lgx Schip1 1423038_at CR only Stx6 1423044_at Lgx only Prosc 1423047_at Lgx only Tollip 1423049_a_at Lgx only Tpm1 1423067_at Lgx only Cdk5rap3 1423072_at Res & Lgx 6720475J19Rik 1423073_at Res & Lgx Cmpk 1423078_a_at Res only Sc4mol 1423083_at Lgx only Rab33b 1423085_at Lgx only Efnb3 1423086_at Lgx only Npc1 1423104_at Lgx only Irs1 1423107_at Res & Lgx Ube2b 1423115_at Lgx only St6galnac6 1423116_at Lgx only Dom3z 1423117_at Lgx only Pum1 1423120_at Lgx only Ide 1423145_a_at Lgx only Tcap 1423159_at Lgx only Dld 1423167_at Lgx only Mobkl3 1423185_a_at Lgx only Ubap1 1423195_at Lgx only Hiat1 1423210_a_at Lgx only Nola3 1423238_at CR only Itgb1bp2 1423245_at Lgx only Cops7a 1423247_at Res & Lgx Txndc4 1423283_at Res only Pitpna 1423289_a_at Lgx only 1810029B16Rik 1423296_at Res & Lgx Psmd8 1423315_at Res only Bbc3 1423332_at Lgx only Sdcbp 1423347_at Lgx only Sec23a 1423362_at Lgx only Sort1 1423365_at Lgx only Cacna1g 1423368_at Res only Laptm4a 1423369_at Lgx only Fmr1 1423373_at Lgx only Rpp30 1423383_a_at Lgx only Osbpl9 1423393_at Res & Lgx Clic4 1423407_a_at Res & Lgx Fbln2 1423423_at Res & Lgx Pdia3 1423425_at Lgx only 1300012G16Rik 1423431_a_at Res & Lgx Mybbp1a 1423440_at Lgx only 1110001A07Rik 1423441_at Lgx only Tfb2m 1423448_at Res & Lgx Rab11b 1423449_a_at Lgx only Actn4 1423459_at Lgx only Cops2 1423474_at Res & Lgx Top1 1423485_at Lgx only Rad54l2 1423486_at Res & Lgx Cript 1423490_at Lgx only Fbxo3 1423494_at CR only 2310042E22Rik 1423512_at Lgx only AW209491 1423529_at Lgx only G6pc2 1423535_at Lgx only LOC100047794 1423557_at Res & Lgx Ifngr2 1423565_at Lgx only Paics 1423577_at CR only Ankrd32 1423588_at Res & Lgx Arpc4 1423599_a_at Lgx only Pdcl 1423609_a_at Lgx only Mgat1 1423611_at CR only Akp2 1423620_at Lgx only Cenpq 1423629_at Lgx only Dnm2 1423642_at CR & Res Tubb2c 1423643_at Lgx only Ddx39 1423647_a_at Res only Zdhhc3 1423648_at CR only Pdia6 1423657_at Res & Lgx Cdipt 1423662_at Res & Lgx Atp6ap2 1423663_at CR only Flcn 1423667_at All Mat2a 1423669_at Lgx only Col1a1 1423670_a_at CR & Lgx Srpr 1423676_at Lgx only Atp5h 1423685_at Lgx only Aars 1423694_at CR only Kctd10 1423697_at Lgx only Psmd6 1423710_at Lgx only Dlst 1423711_at Res & Lgx Ndufaf1 1423725_at Lgx only Pls3 1423734_at Lgx only Rac1 1423737_at Lgx only Ndufs3 1423753_at CR only Bambi 1423759_a_at Res & Lgx Tmco1 1423766_at Res & Lgx Pak1ip1 1423767_at Lgx only 2810410M20Rik 1423771_at Lgx only Prkcdbp 1423773_at Lgx only Gpbp1 1423780_at Lgx only Hibadh 1423785_at Lgx only Egln1 1423790_at Lgx only Dap 1423793_at Res & Lgx D2Ertd391e 1423810_at CR only Ppme1 1423822_a_at Lgx only Tmem168 1423845_at Lgx only Csdc2 1423847_at Res & Lgx Ncapd2 1423849_a_at Lgx only Clk3 1423852_at Lgx only Tmem46 1423857_at Res & Lgx Mrpl30 1423881_at Lgx only Saps3 1423882_at Lgx only Rfwd3 1423883_at Lgx only Acsl1 1423892_at CR only Apbb1 1423896_a_at Lgx only Rnf187 1423907_a_at Lgx only Ndufs8 1423909_at Lgx only Tmem176a 1423919_at Lgx only BC023882 1423927_at Res & Lgx Slc35b2 1423939_a_at Lgx only Yif1a 1423947_at Res & Lgx 1110008P14Rik 1423951_at Lgx only Tm2d3 1423958_a_at Lgx only Ttc33 1423960_at Res & Lgx Mboat5 1423961_at Res & Lgx LOC100045629 1423967_at Lgx only Palm 1423969_at All Nup37 1423972_at Lgx only Etfa 1423973_a_at Lgx only Arf3 1423978_at Lgx only Sbk1 1423991_at Lgx only Nol14 1423993_at Lgx only Atp6v1f 1424000_a_at Lgx only Rps11 1424002_at Res & Lgx Pdcl3 1424005_at Lgx only B230219D22Rik 1424010_at Lgx only Mfap4 1424025_at Res & Lgx BC013529 1424027_at Res only Pxn 1424028_at Lgx only 5830457O10Rik 1424033_at Res & Lgx Sfrs7 1424036_at Lgx only Prpf6 1424038_a_at Lgx only 2310044H10Rik 1424040_at Lgx only Mtap7d1 1424053_a_at Res & Lgx Tcf25 1424054_at Res & Lgx Btbd2 1424058_at Lgx only Prrc1 1424066_at Lgx only Dus3l 1424077_at Res only Gdpd1 1424081_at Res & Lgx Pcgf6 1424099_at Lgx only 2310016C16Rik 1424101_at Res & Lgx Hnrpl 1424105_a_at Lgx only Pttg1 1424109_a_at Res & Lgx Glo1 1424115_at CR & Lgx Ppp5c 1424121_at Lgx only Commd1 1424126_at CR & Res Alas1 1424134_at Lgx only Rspry1 1424138_at Lgx only Rhbdf1 1424139_at Lgx only Rap1a 1424140_at Res only Gale 1424141_at Lgx only Hectd1 1424147_at Res & Lgx Ahsa1 1424149_at CR only Nsmce2 1424150_at Lgx only Gdpd5 1424151_at Res & Lgx Jtv1 1424154_a_at Lgx only Isca2 1424159_at Res & Lgx 1300010M03Rik 1424160_at Lgx only Alg5 1424162_at CR only Trim29 1424163_at Lgx only Rmnd5b 1424167_a_at Lgx only Pmm1 1424175_at CR & Lgx Tef 1424178_at Lgx only Tmem38a 1424179_at Lgx only Plekhj1 1424184_at Lgx only Acadvl 1424191_a_at Lgx only Tmem41a 1424209_at Lgx only Rars2 1424210_at Res & Lgx Erlin1 1424211_at CR & Lgx Slc25a33 1424216_a_at Lgx only Papola 1424223_at Lgx only 1700020C11Rik 1424236_at Lgx only Tbc1d10b 1424237_at Res only Zfp639 1424247_at Lgx only Erc1 1424249_a_at All Arhgap9 1424255_at Res & Lgx Supt5h 1424258_at Lgx only Polr2d 1424261_at Res & Lgx Zfp672 1424274_at Res & Lgx Vdp 1424276_at Lgx only Snx16 1424280_at Res & Lgx Mospd1 1424303_at Lgx only Depdc7 1424309_a_at Res & Lgx Mocs2 1424318_at Lgx only 1110067D22Rik 1424321_at Lgx only Rfc4 1424324_at Lgx only Esco1 1424346_at Lgx only Ppp6c 1424349_a_at Res & Lgx Lpgat1 1424356_a_at Lgx only Metrnl 1424359_at Lgx only Oplah 1424361_at Lgx only BC019943 1424372_at Res & Lgx Mrpl32 1424374_at Lgx only Gimap4 1424377_at Lgx only BC003885 1424380_at Lgx only Vps37b 1424384_a_at Lgx only Znrf1 1424390_at Lgx only Nupl1 1424391_at CR & Lgx Nrd1 1424403_a_at Lgx only Rufy3 1424406_at Lgx only Bcl2l13 1424408_at Lgx only Lims2 1424416_at Lgx only Nkiras2 1424424_at Lgx only Slc39a1 1424430_at Res only Mterfd2 1424433_at Res & Lgx Msrb2 1424434_at Res & Lgx BC024814 1424447_at Lgx only 1700030K09Rik 1424461_at Res & Lgx Dctn2 1424463_at Res & Lgx 2210010L05Rik 1424465_at Lgx only Ccdc58 1424467_at Lgx only Phldb1 1424473_at Lgx only Polr2h 1424479_at Lgx only Cst8 1424500_at Lgx only Utp6 1424505_at Lgx only Rmnd1 1424510_at Lgx only Nudt6 1424517_at CR only Ccdc12 1424520_at Res only 2010305A19Rik 1424526_a_at Lgx only Tgds 1424527_at Lgx only Ppp2r2d 1424531_a_at Lgx only Tcea3 1424539_at Res & Lgx Ubl4 1424541_at Res & Lgx Tmem70 1424545_at Res & Lgx BC003965 1424553_at Lgx only Hhatl 1424559_at Lgx only Rpap2 1424562_a_at Lgx only Slc25a4 1424564_at Lgx only 2410001C21Rik 1424572_a_at Lgx only H2afy 1424585_at Lgx only Ranbp10 1424594_at Lgx only Lgals7 1424595_at Lgx only F11r 1424598_at Lgx only Ddx6 1424614_at Lgx only Frag1 1424635_at Lgx only Eef1a1 1424639_a_at Lgx only Hmgcl 1424642_at Res & Lgx Thoc1 1424643_at Lgx only Tcof1 1424644_at Lgx only Tbcc 1424669_at Res & Lgx Zfyve21 1424682_at Lgx only Atpbd1c 1424683_at Lgx only 1810015C04Rik 1424686_at Lgx only Heatr6 1424700_at Lgx only Tmem38b 1424715_at All Retsat 1424720_at Lgx only Mgat4b 1424727_at Lgx only Ccr5 1424728_at CR & Lgx BC011248 1424736_at Res & Lgx Eef2 1424744_at Lgx only Sds 1424745_at Lgx only Agxt2l2 1424746_at Res & Lgx Kif1c 1424749_at Res & Lgx Wdfy1 1424776_a_at Lgx only Slc25a28 1424777_at Lgx only Wdr21 1424790_at Lgx only Slc25a42 1424791_a_at Lgx only Bcam 1424795_a_at Res only 1700001O22Rik 1424819_a_at Lgx only Ric8 1424827_a_at Lgx only Csnk1a1 1424842_a_at Lgx only Arhgap24 1424850_at Lgx only Map3k1 1424873_at Res & Lgx Rnf2 1424878_at CR & Lgx Lrch4 1424898_at CR only Slc10a1 1424912_at Lgx only Slc25a17 1424918_at Res & Lgx Tbc1d19 1424929_a_at Lgx only Trim26 1424942_a_at CR only Myc 1424954_a_at Lgx only Pip5k1c 1424956_at Lgx only Ahdc1 1424978_at Res only Odf4 1424988_at Lgx only Mylip 1424990_at Lgx only Tmem142a 1424996_at Lgx only Cflar 1425024_at CR only E430018J23Rik 1425057_at Res only Pbld 1425079_at CR only Tm6sf2 1425114_at Res & Lgx Rbbp6 1425143_a_at Lgx only Ndufs1 1425158_at Res & Lgx Tbx20 1425164_a_at Lgx only Phkg1 1425189_a_at Res & Lgx Mrpl15 1425214_at Lgx only P2ry6 1425225_at Lgx only Fcgr4 1425228_a_at Lgx only Dguok 1425243_at Lgx only Cd207 1425257_at Lgx only Acot5 1425270_at Res & Lgx Kif1b 1425274_at Res & Lgx Asph 1425314_at Res only Gpr98 1425332_at Lgx only Zfp106 1425333_at Lgx only Rab43 1425340_a_at CR & Lgx Ptpra 1425341_at Lgx only Kcnk3 1425350_a_at Res & Lgx Myef2 1425455_a_at Lgx only Churc1 1425480_at Res & Lgx Cnot6l 1425492_at Res & Lgx Bmpr1a 1425519_a_at Res & Lgx Cd74 1425521_at Lgx only Paip1 1425558_at Res only Klc3 1425589_at Lgx only Hsd17b13 1425617_at Lgx only Dhx9 1425639_at Lgx only Centa2 1425646_at Lgx only BC016495 1425674_a_at Lgx only Ssu72 1425677_a_at Lgx only Ank1 1425682_a_at Lgx only Tprkb 1425702_a_at Lgx only Enpp5 1425706_a_at Lgx only Ddb2 1425718_a_at Lgx only Ivns1abp 1425742_a_at Lgx only Tsc22d1 1425753_a_at Res only Ung 1425760_a_at Lgx only Pitpnm1 1425764_a_at Lgx only Bcat2 1425780_a_at Lgx only Tmem167 1425792_a_at Res & Lgx Rorc 1425795_a_at Res & Lgx Map3k7 1425826_a_at Lgx only Sorbs1 1425894_at CR only Mrgprf 1425895_a_at Lgx only Id1 1425904_at Res only Satb2 1425930_a_at Lgx only Mlx 1425933_a_at Res & Lgx Nt5c2 1425940_a_at Lgx only Ssbp3 1425978_at Res & Lgx Myocd 1425993_a_at Res & Lgx Hsp110 1426000_at Lgx only Oxtr 1426016_a_at Lgx only Tro 1426068_at Lgx only Slc7a4 1426089_a_at Lgx only BC003331 1426100_a_at Lgx only Tk2 1426114_at Res & Lgx Hnrpab 1426118_a_at Lgx only Tomm40 1426179_a_at Lgx only Twsg1 1426187_a_at Lgx only Hax1 1426195_a_at Lgx only Cst3 1426235_a_at Res & Lgx Glul 1426241_a_at Lgx only Scmh1 1426249_at Res & Lgx Adrbk1 1426254_at Lgx only Tm2d1 1426257_a_at Res & Lgx Sars 1426263_at Lgx only Cadm4 1426269_at Res & Lgx Sybl1 1426277_at Lgx only C730025P13Rik 1426279_at Lgx only 5830415L20Rik 1426285_at Lgx only Lama2 1426286_at Lgx only Noc3l 1426297_at Lgx only Tcfe2a 1426307_at Res & Lgx Cyb5r4 1426337_a_at CR & Lgx Tead4 1426344_at Lgx only Gle1l 1426347_at CR only 2010321M09Rik 1426353_at Lgx only Stat6 1426380_at Lgx only Eif4b 1426386_at Res & Lgx Rpl7l1 1426390_a_at Lgx only Arf1 1426398_at Lgx only Ube2w 1426400_a_at Res & Lgx Capns1 1426406_at Res & Lgx Setd8 1426416_a_at Res & Lgx Yipf4 1426423_at Res & Lgx Shmt2 1426436_at Lgx only Tmem159 1426440_at Lgx only Dhrs7 1426444_at Res only Rhbdd2 1426445_at Lgx only Ctage5 1426446_at Lgx only 6430548M08Rik 1426452_a_at Lgx only Rab30 1426455_at Lgx only Sdccag10 1426457_at Lgx only Slmap 1426468_at Res only 0610037L13Rik 1426477_at Lgx only Rasa1 1426480_at Lgx only Sbds 1426481_at Res & Lgx Klhl22 1426482_at Lgx only Prkrir 1426495_at Lgx only 2410042D21Rik 1426539_at Lgx only Usp11 1426567_a_at Res only Pqlc1 1426586_at Lgx only Slc25a11 1426596_a_at All Smn1 1426607_at Lgx only EG633640 1426613_a_at Lgx only Snrpb2 1426614_at Lgx only Prkcbp1 1426624_a_at Res & Lgx Ypel3 1426629_at Lgx only Dhx8 1426643_at Lgx only Elp3 1426646_at Lgx only 9130011J15Rik 1426648_at Lgx only Mapkapk2 1426670_at Res & Lgx Agrn 1426671_a_at Lgx only Rbm39 1426675_at Lgx only Tomm70a 1426681_at Lgx only Unk 1426682_at Lgx only LOC100046343 1426688_at Lgx only Sdha 1426690_a_at Res & Lgx Srebf1 1426691_at Lgx only Tjap1 1426700_a_at Lgx only Usp52 1426717_at Res & Lgx Nipa2 1426718_at Res & Lgx Skiv2l2 1426731_at Lgx only Des 1426741_a_at Lgx only Fastkd2 1426743_at Lgx only Appl2 1426752_at Res only Phf17 1426760_at Res & Lgx Ipo8 1426773_at Lgx only Mfn1 1426774_at Res & Lgx Parp12 1426794_at Lgx only Ptprs 1426799_at Lgx only Rab8b 1426819_at Lgx only LOC100048439 1426820_at Lgx only 2610507B11Rik 1426830_a_at Lgx only Ahcyl1 1426833_at Lgx only Eif4g3 1426854_a_at Lgx only Set 1426857_a_at Lgx only Hsdl2 1426866_at Lgx only Chst14 1426886_at Res & Lgx Cln5 1426895_at Res & Lgx Zfp191 1426898_at Res only Map3k7ip1 1426900_at Lgx only Jmjd1c 1426948_at Res & Lgx Tpr 1426952_at Lgx only Arhgap18 1426964_at Lgx only 3110003A17Rik 1426965_at Lgx only Rap2a 1426969_at Res & Lgx Trim23 1426976_at Lgx only Usp47 1426979_at Lgx only Mlxip 1426982_at Res & Lgx Flywch1 1426984_at Res & Lgx 2310067B10Rik 1426992_at Res & Lgx Xpr1 1427028_at Lgx only Lgr6 1427039_at Lgx only Epn1 1427040_at Lgx only Mdfic 1427045_at Lgx only Synpo 1427051_at Res & Lgx Tnks1bp1 1427058_at Res only Eif4a1 1427073_at Res only Lace1 1427084_a_at Lgx only Map4k5 1427099_at Res only Maz 1427117_at Lgx only Mtmr3 1427120_at Lgx only Zfp26 1427129_a_at Lgx only Hnrpr 1427132_at Lgx only Sbf2 1427139_at Lgx only Adamts10 1427144_at Res & Lgx Hnrpll 1427146_at Res & Lgx AI790298 1427165_at Res & Lgx Il13ra1 1427166_a_at Lgx only Spg7 1427170_at All Psma8 1427197_at Lgx only Atr 1427201_at Lgx only Mustn1 1427228_at Lgx only Palld 1427239_at CR & Lgx Ift122 1427240_at Lgx only Dock6 1427241_at Lgx only Papolg 1427260_a_at Res & Lgx Tpm3 1427266_at All Pbrm1 1427296_at Res & Lgx BC010304 1427312_at Lgx only Cmya5 1427314_at Res & Lgx Tmed7 1427319_at CR & Lgx A230046K03Rik 1427342_at Res & Lgx Fastkd1 1427395_a_at Lgx only Aldh1a3 1427418_a_at Lgx only Hif1a 1427432_a_at Lgx only Sfrs10 1427447_a_at Res & Lgx Triobp 1427490_at Lgx only Abcb7 1427529_at Res only Fzd9 1427555_at Lgx only Mll2 1427557_at Lgx only Alg12 1427604_a_at Lgx only Atp9a 1427661_a_at Res & Lgx Tssc4 1427689_a_at Lgx only Tnip1 1427720_a_at Lgx only Rrp1 1427728_at CR only Chrng 1427735_a_at CR & Res Acta1 1427873_at Lgx only Defcr15 1427874_at Lgx only Zfp313 1427876_at Lgx only Zc3h15 1427886_at Lgx only Pom121 1427888_a_at CR & Lgx Spna2 1427894_at Lgx only Vasn 1427898_at Lgx only Rnf6 1427901_at Lgx only Mrps18c 1427903_at Res & Lgx Phpt1 1427913_at Lgx only Rwdd1 1427918_a_at Lgx only Rhoq 1427929_a_at Lgx only Pdxk 1427943_at Lgx only Acyp2 1427947_at CR only BC028440 1427955_a_at Lgx only Deb1 1427971_at Lgx only Cdc73 1427983_at Lgx only Suhw3 1427990_at Lgx only Usp45 1427996_at Lgx only BC028528 1427997_at Res & Lgx 1110007M04Rik 1428029_a_at Res & Lgx H2afv 1428061_at Res & Lgx Hat1 1428064_at Lgx only Centd2 1428071_at Lgx only 1110038D17Rik 1428083_at CR & Lgx 2310043N10Rik 1428084_at Lgx only Krr1 1428100_at Lgx only Sfrs1 1428103_at CR & Lgx Adam10 1428124_at Lgx only Gtf2e1 1428128_at Res & Lgx 4921506J03Rik 1428134_at Lgx only Coq9 1428143_a_at Res & Lgx Pnpla2 1428158_at Res & Lgx Akt1s1 1428160_at Lgx only Ndufab1 1428173_at Lgx only Eml2 1428179_at Lgx only Ndufv2 1428182_at Lgx only Prpsap1 1428198_at Lgx only Adal 1428201_at CR only 2310036O22Rik 1428206_at Res only Ccdc69 1428213_at Res & Lgx Nsmce4a 1428230_at CR only Prkcn 1428235_at Lgx only Sdhd 1428236_at Lgx only Acbd5 1428244_at Lgx only Larp1 1428250_at Lgx only Gper 1428251_at Lgx only Smchd1 1428253_at Res & Lgx Chmp2b 1428256_at Res & Lgx 2310047H23Rik 1428260_at Res & Lgx Spg3a 1428277_at Lgx only Otud6b 1428282_at Lgx only Tbce 1428299_at Res & Lgx Dyrk1a 1428307_at Lgx only Zdhhc13 1428316_a_at Res & Lgx Fundc2 1428332_at CR & Lgx Pik3ip1 1428335_a_at Lgx only Scfd1 1428357_at Res only 2610019F03Rik 1428365_a_at Lgx only Lonp1 1428366_at All 1600027N09Rik 1428370_at CR only 1500011B03Rik 1428380_at Res & Lgx 0610007C21Rik 1428382_at Lgx only Smarcc2 1428391_at Lgx only Rab3il1 1428395_at Lgx only Smurf1 1428405_at Lgx only Hcfc1r1 1428412_at Lgx only Tm9sf3 1428421_a_at Lgx only Glod4 1428423_at Lgx only Pcgf3 1428427_at CR only Fbxl2 1428431_at Res & Lgx 2310047A01Rik 1428436_at Res & Lgx Lsm14a 1428440_at Lgx only Slc25a12 1428441_at Lgx only Cisd2 1428443_a_at Lgx only Rap1gap 1428465_at Lgx only Tmem147 1428468_at All 3110043O21Rik 1428476_a_at Lgx only Elac2 1428494_a_at Lgx only Polr2i 1428495_at Res & Lgx 2410003K15Rik 1428503_a_at Lgx only Nkiras1 1428505_at Lgx only Ccdc90b 1428507_at Lgx only Hdhd2 1428508_at Lgx only Tbc1d2b 1428510_at Lgx only Lphn1 1428515_at Lgx only 2410012H22Rik 1428519_at Lgx only 2610528E23Rik 1428540_at Lgx only 3321401G04Rik 1428544_at Res & Lgx 0610007L01Rik 1428549_at Lgx only Ccdc3 1428551_at All Trmt11 1428552_at Res & Lgx 2610001J05Rik 1428554_a_at Lgx only 1810035L17Rik 1428564_at Lgx only Zfp579 1428580_at Lgx only Blvra 1428585_at Lgx only Actn1 1428587_at Res & Lgx Tmem41b 1428589_at Lgx only Mrpl41 1428593_at Res only 1700029F09Rik 1428594_at Lgx only Garnl1 1428598_at All Tbc1d7 1428613_at Res only Ldhd 1428615_at CR only P2ry5 1428617_at Res & Lgx Hcfc2 1428626_at Lgx only Lysmd2 1428651_at CR & Lgx Klhl24 1428652_at Res & Lgx 0610010F05Rik 1428668_at Lgx only Acbd3 1428682_at CR only Zc3h6 1428691_at Lgx only Chd2 1428697_at Lgx only Dpp8 1428707_at Lgx only Ptms 1428715_at Res & Lgx 2810423A18Rik 1428722_at Lgx only Ckmt2 1428723_at Lgx only 2310047M10Rik 1428728_at CR only Ddx51 1428731_at Lgx only Usp54 1428748_at Lgx only 5830428H23Rik 1428749_at Res & Lgx Dmxl2 1428758_at CR & Res Tmem86a 1428767_at Lgx only Gsdmdc1 1428769_at Res only Tatdn3 1428782_a_at Res & Lgx Uqcrc1 1428786_at Res only Nckap1l 1428789_at CR only Ralgps2 1428791_at Lgx only Ube2h 1428807_at Lgx only Pabpc3 1428810_at Lgx only 2700097O09Rik 1428812_at Res only 1700040L02Rik 1428829_at CR & Lgx 6820401H01Rik 1428831_at Lgx only 6230429P13Rik 1428835_at Lgx only Myh14 1428845_at Res & Lgx Bclaf1 1428848_a_at Lgx only Macf1 1428884_at Lgx only Tmem57 1428890_at Lgx only Fem1c 1428897_at Res & Lgx 2610029I01Rik 1428899_at Res & Lgx Tmem182 1428914_at Res & Lgx 2310014D11Rik 1428919_at Res & Lgx Fgfr1op 1428926_at Lgx only 1110003O08Rik 1428945_at Res only Ube1l2 1428949_at Lgx only Xpot 1428982_at Res & Lgx Atad2b 1428998_at Lgx only Phf3 1429001_at Res only Pir 1429024_at Lgx only Rbm20 1429028_at Lgx only Dock11 1429034_at Lgx only Eme2 1429042_at Res & Lgx 2010200O16Rik 1429057_at Res & Lgx Narg1l 1429070_at Lgx only 4933440H19Rik 1429085_at Lgx only Vezf1 1429103_at Res & Lgx Tomm22 1429107_at Lgx only Zfp650 1429119_at Lgx only Iah1 1429121_at Lgx only 4921517N04Rik 1429137_at Lgx only 2810422O20Rik 1429144_at Res only Prei4 1429146_at Lgx only 6620401M08Rik 1429155_at Res only 4933411K20Rik 1429160_at Res & Lgx Mtif3 1429183_at Lgx only Pkp2 1429186_a_at Lgx only Cdadc1 1429188_at Lgx only Cox11 1429194_at Lgx only Tigd2 1429196_at Lgx only Rabgap1l 1429206_at Lgx only Rhobtb1 1429209_at CR only Col23a1 1429223_a_at Res & Lgx Hfe2 1429243_at Res & Lgx 1110054O05Rik 1429253_at Lgx only Zmym4 1429264_at Lgx only C030044B11Rik 1429278_at Res only Nubpl 1429281_at Res & Lgx 2610008E11Rik 1429300_at Lgx only Ankrd9 1429321_at Lgx only Rnf149 1429328_at Lgx only Nsfl1c 1429335_at Lgx only Snapc1 1429352_at CR only Mocos 1429362_a_at Res & Lgx Sf3b2 1429364_at Lgx only 4930579G24Rik 1429367_at Lgx only Wipi2 1429375_at Lgx only Anapc10 1429395_at Lgx only Gstcd 1429400_at Lgx only Clcn5 1429407_at Lgx only Pex11c 1429413_at Res & Lgx Cpm 1429425_at Res & Lgx Rnf139 1429454_at Res & Lgx Gapvd1 1429460_at CR only Gpr115 1429486_at CR only Pfkfb2 1429487_at Lgx only Ppp1r12a 1429505_at CR & Lgx 2310076G13Rik 1429514_at Lgx only Ppap2b 1429521_at Lgx only Alkbh8 1429532_at Res only Morc2a 1429534_a_at Lgx only Immt 1429553_at Lgx only Cilp2 1429556_at Lgx only 2610024B07Rik 1429570_at Res only Mlkl 1429621_at Lgx only Cand2 1429648_at Lgx only Slc35a3 1429681_a_at Lgx only Gpsn2 1429698_at Res & Lgx Mterf 1429710_at Res & Lgx Styx 1429723_at Res & Lgx 6330409N04Rik 1429764_at CR only 1500005K14Rik 1429771_at Lgx only 3110073H01Rik 1429783_at Res & Lgx Pdlim5 1429819_at Lgx only Nmnat1 1429836_at CR only Ugcgl2 1429860_at CR only LOC677447 1429888_a_at Lgx only Hspb2 1429915_at Lgx only 4930426L09Rik 1429918_at CR only Arhgap20 1429961_at CR & Lgx 1700021C14Rik 1429990_at Lgx only Hyal4 1430000_at CR only B230117O15Rik 1430045_at CR & Res Tsnax 1430078_a_at Lgx only Ogg1 1430089_at Lgx only 5830469G19Rik 1430095_at Lgx only D930020B18Rik 1430123_a_at Lgx only Akr1a4 1430137_at Res only LOC100043489 1430170_at Res only Bbs10 1430224_at Res only Wfdc3 1430253_at Lgx only 2900006B11Rik 1430292_a_at Res & Lgx 1810030N24Rik 1430309_at Res & Lgx Nipbl 1430378_at Res & Lgx 2900011G08Rik 1430388_a_at Lgx only Sulf2 1430474_a_at Res & Lgx Mtch2 1430518_at Lgx only 5430402E10Rik 1430519_a_at Lgx only Cnot7 1430527_a_at Res & Lgx Rnf167 1430544_at Lgx only 5830404H04Rik 1430656_a_at Res & Lgx Asnsd1 1430676_at CR & Lgx Col19a1 1430685_at Res only 6330503C03Rik 1430736_at Lgx only 9030411M15Rik 1430768_at Lgx only 9530018H14Rik 1430770_at Res & Lgx 3110080E11Rik 1430781_at Lgx only Ak7 1430799_at Res & Lgx 5830432E09Rik 1430818_at CR only Tmc1 1430835_at CR only Ccdc125 1430883_at CR only 4933402C05Rik 1430910_at CR only 4930544L04Rik 1430999_a_at Res & Lgx Scoc 1431043_at Lgx only Kbtbd5 1431255_at CR only Calr3 1431287_at CR only Pcm1 1431293_a_at Res & Lgx Cldnd1 1431302_a_at CR & Lgx Nudt7 1431322_at Lgx only Igsf3 1431415_a_at Lgx only Tbpl1 1431428_a_at Lgx only Nosip 1431429_a_at Lgx only Arl4a 1431473_at Lgx only 5330423I11Rik 1431498_at Res only 9530097N15Rik 1431551_at Lgx only 2610028D06Rik 1431561_a_at Res only Dhx34 1431587_at Res only Ccdc7 1431610_at Res only 5330439A09Rik 1431618_a_at CR & Res D14Ertd581e 1431619_a_at Lgx only Dtnbp1 1431679_at Res only 2510042H12Rik 1431746_a_at Lgx only Ube1c 1431785_at Lgx only Rnaset2a 1431796_at Lgx only 2810430I11Rik 1431804_a_at Res & Lgx Sp3 1431822_a_at Res & Lgx Azi2 1431827_a_at Lgx only Tlk2 1431853_at CR only 4933413C19Rik 1431893_a_at Res & Lgx Pdss1 1431900_a_at CR only Foxa3 1431934_at Lgx only 4930505O20Rik 1431986_at Res only 4933421A08Rik 1431998_at CR only 4930432L08Rik 1432000_a_at Lgx only Dedd 1432016_a_at CR only Idh3a 1432057_a_at Lgx only Prdm5 1432073_at Res & Lgx 1700113I22Rik 1432122_at Lgx only Lrrc44 1432158_a_at Res & Lgx Trappc2 1432207_a_at Lgx only Toe1 1432248_at Lgx only 5430402P08Rik 1432271_a_at Res & Lgx Dcun1d5 1432348_at Lgx only 4930524O07Rik 1432369_at CR & Res 3010027C24Rik 1432420_a_at Lgx only 2310002L09Rik 1432444_a_at Lgx only Eapp 1432457_at Res only 4930448F12Rik 1432466_a_at Lgx only Apoe 1432533_a_at Lgx only Slc35a2 1432543_a_at Res only Klf13 1432560_at Res only 1700127D06Rik 1432590_at CR only 4930573O21Rik 1432625_at Res only 5830487K18Rik 1432626_at Lgx only 5730507A11Rik 1432648_at Res only 4930466F19Rik 1432662_at Res only 0610042E11Rik 1432735_at Lgx only 1700017H01Rik 1432930_at Res only 4930453O09Rik 1433048_at CR only 4933428L01Rik 1433132_at CR only Edaradd 1433148_at CR only 4930513N20Rik 1433164_at Res only 4930570E01Rik 1433207_at Lgx only 5033430J17Rik 1433241_at Lgx only 9430013L17Rik 1433253_at Lgx only 5033423K11Rik 1433314_at Lgx only 4930486A15Rik 1433442_at Lgx only Klhl9 1433464_at Lgx only Ipo13 1433503_at Res & Lgx Zadh1 1433504_at Lgx only Pygb 1433514_at Lgx only Etnk1 1433518_at Lgx only Lcmt2 1433519_at Lgx only Nucks1 1433520_at Lgx only Scap 1433521_at Res & Lgx Ankrd13c 1433522_at Lgx only Pskh1 1433528_at Lgx only Gtf2a2 1433537_at Lgx only 4833408C14Rik 1433539_at Res & Lgx Commd3 1433544_at Lgx only Als2cr2 1433555_at Lgx only Eaf1 1433556_at Res & Lgx Centa1 1433561_at Lgx only Centb2 1433575_at Lgx only Sox4 1433585_at Lgx only Tnpo1 1433597_at Res & Lgx 9430010O03Rik 1433599_at Lgx only Baz1a 1433645_at Lgx only Slc44a1 1433648_at Lgx only Spag9 1433656_a_at Lgx only Gnl3 1433664_at Res & Lgx Ube2q2 1433676_at Res & Lgx Wnk1 1433682_at Lgx only Arhgef17 1433686_at Lgx only Cabin1 1433691_at Res & Lgx Ppp1r3c 1433698_a_at Res & Lgx Txnl4 1433700_at Res & Lgx 4933433P14Rik 1433705_at Lgx only Zfp213 1433712_at Lgx only AW555464 1433717_at All D19Wsu162e 1433718_a_at Lgx only LOC100047028 1433722_at Lgx only Akap13 1433725_at Res & Lgx Acvr1b 1433727_at Lgx only BC038479 1433733_a_at Lgx only Cry1 1433738_at Res & Lgx Papd5 1433741_at Lgx only Cd38 1433746_at Lgx only Wdr3 1433751_at Lgx only Slc39a10 1433760_a_at Lgx only Rhbdd3 1433765_at Lgx only Ube2o 1433770_at Lgx only Dpysl2 1433772_at Res & Lgx Stch 1433790_at CR only Troap 1433794_at Lgx only Setx 1433799_at Lgx only Rdh13 1433808_at Lgx only D330001F17Rik 1433811_at Res & Lgx Mllt6 1433847_at Lgx only D330017J20Rik 1433868_at Lgx only Btbd3 1433875_at Lgx only 4732418C07Rik 1433883_at Lgx only Tpm4 1433891_at Res & Lgx Lgr4 1433897_at Res & Lgx AI597468 1433898_at Lgx only AV025504 1433910_at Lgx only Zcchc6 1433914_at Res & Lgx AI747699 1433918_at Res & Lgx Atg4d 1433922_at Res & Lgx Rab35 1433926_at Res & Lgx Dync1li2 1433931_at Lgx only C030046I01Rik 1433952_at Res & Lgx Tufm 1433953_at Lgx only Zfp277 1433979_at Lgx only Rbms2 1433986_at Lgx only BC024659 1434001_at Res & Lgx Ttc9c 1434008_at Lgx only Scn4b 1434009_at Res & Lgx Grlf1 1434018_at Lgx only BC043098 1434059_at Lgx only B230312A22Rik 1434064_at Res & Lgx Tmem142c 1434066_at Lgx only Gtf3c1 1434067_at Res only AI662270 1434072_at Lgx only Smcr7 1434075_at Res & Lgx BC030336 1434082_at Lgx only Pctk2 1434084_at Lgx only 5730601F06Rik 1434088_at Lgx only Zkscan17 1434096_at Lgx only Slc4a4 1434105_at Lgx only Epm2aip1 1434115_at Lgx only Cdh13 1434131_at Lgx only Rufy1 1434135_at Lgx only B3galnt2 1434138_at Lgx only Prune 1434140_at CR only Mcf2l 1434153_at CR & Lgx Shb 1434174_at Res only Lysmd3 1434200_at Res & Lgx BC010981 1434205_at Res & Lgx Ppp2r5c 1434234_at Lgx only Zfp341 1434238_at Lgx only Taf2 1434248_at Res only Prkch 1434268_at Lgx only Adar 1434271_at Res & Lgx Gba2 1434273_at Lgx only BC034069 1434277_a_at CR only Ypel2 1434278_at Lgx only Mtm1 1434281_at Lgx only 1500034J01Rik 1434283_at Res & Lgx LOC100044968 1434284_at Res & Lgx Bdp1 1434296_at Lgx only BC049349 1434303_at Lgx only Raph1 1434320_at Lgx only Gtf3c4 1434328_at Lgx only Rpl15 1434339_at Res & Lgx Fnbp1l 1434344_at Lgx only Gpkow 1434354_at Lgx only Maob 1434356_a_at Lgx only Psma5 1434372_at Lgx only AW112010 1434378_a_at Lgx only Mxd4 1434387_at Lgx only Itfg3 1434392_at Res & Lgx Usp34 1434402_at Lgx only Samd8 1434405_at Res & Lgx Fnip1 1434422_at CR & Lgx AI428479 1434441_at Lgx only 1110018J18Rik 1434442_at CR only Stbd1 1434461_at Res & Lgx Zfp715 1434487_at Lgx only Mef2d 1434493_at Lgx only 1810022K09Rik 1434511_at Lgx only Phkb 1434516_at Lgx only Pstk 1434518_at Res & Lgx Phka2 1434558_at Lgx only Wdr47 1434565_at Res & Lgx Cgrrf1 1434586_a_at Lgx only Ptdss2 1434597_at Lgx only Larp5 1434604_at Lgx only Eif5b 1434610_at Res & Lgx Plec1 1434613_at Lgx only 1810013L24Rik 1434625_at Lgx only 4930432O21Rik 1434642_at Res & Lgx Hsd17b11 1434647_at Lgx only Egflam 1434648_a_at Lgx only Ccm2 1434655_at Lgx only Foxk1 1434665_at Lgx only Aga 1434671_at Lgx only B230337E12Rik 1434672_at Lgx only Gpr22 1434714_at Lgx only Ero1lb 1434736_at Lgx only Hlf 1434765_at Lgx only Ep300 1434775_at Lgx only Pard3 1434791_at Lgx only Atp6v0a2 1434792_at Lgx only 2010320M18Rik 1434805_at Lgx only Mllt1 1434822_at Lgx only Pphln1 1434824_at Lgx only Baz1b 1434826_at Lgx only Rfesd 1434835_at Lgx only Wapal 1434838_at Lgx only Kcng2 1434864_at Res & Lgx Nipa1 1434891_at Lgx only Ptgfrn 1434896_at Res & Lgx Zfp422−rs1 1434900_at Lgx only Mkl1 1434904_at Res & Lgx Hivep2 1434909_at Res & Lgx Rragd 1434916_at Lgx only Vkorc1l1 1434927_at Lgx only Hspb7 1434930_at Lgx only Tpcn1 1434934_at Res & Lgx Atpaf1 1434936_at Lgx only Hirip3 1434942_at Res & Lgx Esf1 1434944_at Lgx only Dmpk 1434967_at Res & Lgx Zswim6 1434978_at Lgx only 4933403F05Rik 1434981_at Res only E130303B06Rik 1434997_at Lgx only Cdc2l6 1435016_at Lgx only Trak2 1435017_at Lgx only Mel13 1435018_at Lgx only 5930434B04Rik 1435032_at Lgx only Golgb1 1435091_at Lgx only Zfp568 1435117_a_at Lgx only Rbj 1435135_at Res & Lgx Aadacl1 1435153_at Lgx only Btbd6 1435169_at CR only A930001N09Rik 1435180_at Lgx only Podn 1435183_at All Tbkbp1 1435224_at Lgx only Crebbp 1435242_at Res & Lgx Pds5b 1435248_a_at Lgx only Btaf1 1435250_at Res & Lgx Ints8 1435261_at Res & Lgx 4732416N19Rik 1435295_at Res only Dopey1 1435340_at Lgx only Jmjd2a 1435349_at Lgx only Nrp2 1435351_at CR only 2310026E23Rik 1435360_at Lgx only Zfp651 1435377_at Res & Lgx 2410002O22Rik 1435378_at Lgx only 2210020M01Rik 1435386_at Lgx only Vwf 1435437_at Lgx only Setd7 1435441_at Res only Ablim2 1435442_at Res & Lgx Wdsof1 1435443_at Lgx only Eya3 1435461_at Res & Lgx Magi3 1435490_at CR only Hk3 1435505_at Res only Dmwd 1435524_at Lgx only 2010109N14Rik 1435526_at Lgx only Tor1aip2 1435527_at Lgx only Nfic 1435529_at Res & Lgx OTTMUSG00000016644 1435543_at Lgx only LOC100048863 1435547_at Lgx only ENSMUSG00000075401 1435548_at Lgx only Mrs2l 1435549_at Lgx only Trpm4 1435554_at Res & Lgx Tmcc3 1435556_at Lgx only Zfp597 1435589_at Res & Lgx Ccdc85b 1435641_at Res & Lgx 9530018I07Rik 1435655_at Lgx only Snora65 1435674_at Lgx only Rhobtb2 1435679_at Lgx only Optn 1435693_at CR only Mall 1435695_a_at Lgx only A030007L17Rik 1435743_at Res & Lgx Klhl23 1435754_at Res & Lgx Zyg11b 1435768_at Lgx only Arid4b 1435774_at Lgx only AV024533 1435777_at Lgx only E030018N11Rik 1435782_at Lgx only LOC668206 1435808_at Res & Lgx A230051G13Rik 1435813_at Lgx only Mypn 1435864_a_at Res & Lgx 1810063B05Rik 1435874_at Lgx only Prkab2 1435900_at Res & Lgx Zbtb43 1435912_at Lgx only Ubxd7 1435947_at Lgx only 2810455D13Rik 1436014_a_at CR only Rusc1 1436026_at Lgx only Zfp703 1436033_at Lgx only BC031353 1436041_at CR & Lgx LOC100046086 1436045_at Lgx only Tsga10 1436059_at Res & Lgx Rfx1 1436075_at Lgx only Sfrp5 1436081_a_at Lgx only Zfp414 1436112_at Res only AI118078 1436113_a_at Res only St13 1436121_a_at Lgx only Nsmce1 1436122_at Res only Zfp667 1436157_at Lgx only Ccar1 1436188_a_at CR only Ndrg4 1436208_at CR & Lgx Asb1 1436214_at Lgx only 1110028C15Rik 1436215_at Lgx only Ipmk 1436233_at Lgx only Btnl9 1436240_at Lgx only Sost 1436243_at Lgx only Frmd5 1436275_at Lgx only Kcnip2 1436299_at Res & Lgx Gls 1436310_at Lgx only Gemin5 1436332_at Lgx only Hspb6 1436339_at Lgx only 1810058I24Rik 1436342_a_at Lgx only D19Ertd721e 1436367_at Lgx only C130094E24 1436377_at Res only Gpr137 1436408_at Lgx only Rprml 1436425_at Lgx only Ankrd38 1436446_at Res & Lgx 2310007O11Rik 1436505_at CR only Ppig 1436511_at Res & Lgx BC031781 1436521_at Lgx only Slc36a2 1436537_at CR only Zfp629 1436538_at Res & Lgx Ankrd37 1436546_at Res & Lgx Lix1l 1436547_at CR only Dgke 1436562_at Lgx only Ddx58 1436584_at Res & Lgx Spry2 1436594_at Lgx only Zfp719 1436609_a_at Lgx only Lrpap1 1436650_at CR & Lgx Filip1 1436665_a_at Lgx only Ltbp4 1436739_at Lgx only Agtr1a 1436747_at Lgx only 1110014K08Rik 1436797_a_at Lgx only Surf4 1436809_a_at All Spin1 1436817_at Lgx only Exoc5 1436842_at Res & Lgx B230380D07Rik 1436844_at Lgx only AW046287 1436865_at CR only Slc26a11 1436867_at CR only Srl 1436883_at Lgx only Mbtps2 1436918_at Lgx only LOC100044376 1436947_a_at Lgx only Txnl1 1436984_at Lgx only Abi2 1436985_at Res & Lgx Zfp644 1436999_at Res only 5033414K04Rik 1437026_at Lgx only BC057893 1437069_at Lgx only Osbpl8 1437077_at Res & Lgx Dcun1d2 1437092_at Res & Lgx LOC100048376 1437111_at Lgx only Zc3h12c 1437136_at Res only 5830436I19Rik 1437143_a_at All Txndc1 1437148_at CR & Lgx Arpc2 1437149_at Lgx only Slc6a6 1437151_at Lgx only Usp22 1437216_at Lgx only Ccdc88a 1437236_a_at Lgx only Zfp110 1437241_at CR only Klf11 1437283_at Lgx only Tnpo2 1437287_at Res & Lgx 1110020G09Rik 1437290_at Lgx only Impad1 1437354_at Res & Lgx C230091D08Rik 1437382_at Lgx only Acvr2a 1437394_at Lgx only Centg2 1437397_at Res & Lgx Prlr 1437398_a_at All Aldh9a1 1437403_at Lgx only Samd5 1437405_a_at Lgx only Igfbp4 1437426_at Lgx only Wac 1437432_a_at Res only Trim12 1437442_at Res & Lgx Pcdh7 1437449_at Lgx only Rsad1 1437482_at Res & Lgx Srd5a2l2 1437484_at Res & Lgx Zbtb5 1437513_a_at Lgx only Serinc1 1437533_at Res & Lgx Birc4 1437537_at Res & Lgx Casp9 1437704_at Res & Lgx 2900024O10Rik 1437729_at Lgx only Rpl27a 1437740_at Lgx only Plekhm2 1437741_at Lgx only Rab21 1437785_at Lgx only Adamts9 1437869_at Res & Lgx 3222402P14Rik 1437875_at Lgx only Bicd2 1437900_at Lgx only 4930523C07Rik 1437917_at Lgx only D530037H12Rik 1438024_at Res & Lgx Ccdc90a 1438026_at Lgx only Zfp560 1438045_at Lgx only Eea1 1438047_at Res & Lgx Zfp384 1438062_at CR only 4832420A03Rik 1438077_at Lgx only Nlrp4a 1438097_at Lgx only Rab20 1438169_a_at Lgx only Frmd4b 1438195_at Lgx only Gpd1l 1438208_at Res only Taok2 1438213_at Lgx only A830018L16Rik 1438229_at Res only Pggt1b 1438238_at Lgx only 2010315B03Rik 1438241_at Lgx only Rgma 1438258_at CR & Res Vldlr 1438340_at Lgx only A930006D11Rik 1438349_at Lgx only BC043476 1438400_at Lgx only 4632411B12Rik 1438416_at Lgx only Med16 1438422_at Res & Lgx Lrrc20 1438444_at Lgx only Spink10 1438510_a_at Lgx only Hars 1438512_at Res only BC048679 1438532_at Lgx only Hmcn1 1438610_a_at Lgx only Cryz 1438658_a_at All Edg3 1438673_at Lgx only Slc4a7 1438676_at CR & Lgx Mpa2l 1438678_at Lgx only 1500011K16Rik 1438691_at Res only Zzef1 1438693_at Res & Lgx Tmem110 1438895_at Res only A430102J17Rik 1438908_at Lgx only Map3k12 1438909_at Lgx only Sccpdh 1438910_a_at Lgx only Stom 1439008_at Lgx only Zfp319 1439010_at Lgx only Larp4 1439024_at CR only Bag4 1439029_at Lgx only Gpt2 1439055_at Lgx only OTTMUSG−00000001305 1439078_at Lgx only Klhl4 1439143_at CR & Lgx A930018M24Rik 1439153_at Lgx only Ibrdc2 1439189_at CR only D630023B12Rik 1439244_a_at Lgx only Tnrc6a 1439266_a_at Res & Lgx Polr3k 1439364_a_at Lgx only Mmp2 1439397_at All Fmn1 1439460_a_at All Zfp289 1439483_at Res only AI506816 1439488_at Lgx only Dot1l 1439509_at Res only 2900008C10Rik 1439529_at Res & Lgx A430110N23Rik 1439675_at Res only 4933429D07Rik 1439793_at Lgx only Gja3 1439797_at Lgx only Ppard 1439815_at Lgx only Heatr5b 1439821_at Res only Lrp2bp 1440018_at Lgx only A330043J11Rik 1440096_at Lgx only Ecm2 1440143_at Lgx only Pigz 1440232_at Res only EG622645 1440234_at Lgx only 1810012P15Rik 1440279_at Lgx only Txndc10 1440335_at Lgx only LOC100046468 1440478_at Res only LOC100047601 1440480_at Lgx only AB182283 1440520_a_at CR only 1700051A21Rik 1440537_at Res only Kcnv2 1440542_at Res only 7420416P09Rik 1440561_at Lgx only C87259 1440739_at CR only Vegfc 1440781_at CR only B830007D08Rik 1440831_at Res only Bach1 1440838_at Lgx only AI852064 1440841_at Lgx only BB217526 1440849_at CR only 6330417G04Rik 1440874_at CR only Slco5a1 1440908_at Lgx only D030063E12 1440934_at Lgx only AW742931 1440969_at All BC030308 1441001_at Lgx only AI225934 1441075_at Lgx only Nostrin 1441081_a_at Lgx only 1110038B12Rik 1441139_at CR only ENSMUSG−00000071543 1441174_a_at Res & Lgx Lmln 1441229_at Res & Lgx D230019N24Rik 1441266_at Res & Lgx Strn3 1441320_a_at Res & Lgx AI413194 1441438_at CR only Gpc6 1441536_at Lgx only Hmgcs1 1441590_at Lgx only Kcnj5 1441970_at Lgx only E430010N07Rik 1441987_at Res & Lgx Mbd5 1442002_at Lgx only 7030402D04Rik 1442027_at Lgx only Nbeal1 1442050_at Res & Lgx Zfp608 1442064_at Res & Lgx AW556556 1442090_at Res only 8030463A06Rik 1442174_at Lgx only Tspan18 1442186_at Res & Lgx LOC100045002 1442362_at Res & Lgx Gm104 1442434_at Res only D8Ertd82e 1442659_at Lgx only Pcdh9 1442695_at Lgx only C030007I01Rik 1442732_at CR only Hadhb 1442757_at CR & Res Lrch1 1442867_at Res only Megf11 1442926_at Lgx only 1700011B04Rik 1443103_at CR only D830046C22Rik 1443416_at Lgx only C79741 1443483_at Lgx only Xlr5a 1443632_at CR only Obscn 1443682_at Res only AI662476 1443854_at Lgx only Hand2 1443856_at Lgx only Rabep1 1443896_at Lgx only Tbc1d5 1443932_at Res & Lgx Klhdc1 1443935_at Res only BC032203 1444041_at Lgx only AU041133 1444112_at Lgx only ENSMUSG−00000074466 1444217_at Lgx only Mrpl38 1444254_at CR only Tns4 1444294_at Lgx only 4930551A22Rik 1444370_at CR only C77058 1444456_at Lgx only 9030425P06Rik 1444494_at All Kbtbd10 1444537_at Lgx only AI429363 1444684_at Lgx only 8030475D13Rik 1444766_at Lgx only Atxn7l1 1445191_at CR only Exdl1 1445459_at Lgx only Sstr5 1446062_at Res only B830028B13Rik 1446214_at CR only D430018E03Rik 1446678_at Lgx only D14Ertd16e 1446781_at CR only D8Ertd54e 1446812_at Res & Lgx LOC100040515 1446842_at CR only D4Ertd571e 1447035_at Lgx only A230091C14Rik 1447095_at Lgx only C86942 1447923_at Lgx only 1810026B05Rik 1447967_at Res only Tmem69 1447981_at CR only C78441 1448091_at CR & Lgx D15Ertd50e 1448100_at Res & Lgx 4833439L19Rik 1448116_at Res & Lgx Ube1x 1448122_at CR & Lgx Tcp1 1448143_at Lgx only Aldh2 1448145_at Lgx only Wwp2 1448148_at Res & Lgx Grn 1448153_at Lgx only Cox5a 1448154_at Lgx only Ndrg2 1448163_at Lgx only Gnpda1 1448167_at Lgx only Ifngr1 1448174_at Lgx only Cul1 1448181_at CR only Klf15 1448185_at Lgx only Herpud1 1448188_at Lgx only Ucp2 1448189_a_at Lgx only Flii 1448196_at Res & Lgx Mat2b 1448198_a_at Lgx only Ndufb8 1448199_at Res only Ankrd10 1448206_at Lgx only Psma2 1448208_at Lgx only Smad1 1448209_a_at Lgx only Slc22a17 1448212_at Lgx only Tnfsf5ip1 1448221_at CR only Bat1a 1448224_at Lgx only Tfam 1448225_at Lgx only Gpaa1 1448240_at Lgx only Mbtps1 1448242_at Lgx only Sec61a1 1448244_at Lgx only Lypla1 1448252_a_at Lgx only Eef1b2 1448258_a_at Lgx only Spcs1 1448269_a_at Res & Lgx Klhl13 1448276_at Lgx only Tspan4 1448284_a_at Lgx only Ndufc1 1448287_at Lgx only Rpo1−3 1448304_a_at Res & Lgx Rab6 1448313_at Lgx only Tpp1 1448325_at Res & Lgx Myd116 1448327_at Lgx only Actn2 1448330_at Res & Lgx Gstm1 1448336_at Lgx only Drg1 1448339_at Res & Lgx Tmem30a 1448341_a_at Lgx only Stxbp2 1448345_at Lgx only Tomm34 1448346_at CR only Cfl1 1448351_at Lgx only Coro1b 1448356_at Lgx only Ube2d2 1448362_at Lgx only Dnajc7 1448363_at Res & Lgx Yap1 1448365_at Res & Lgx Exosc7 1448379_at Res only Pot1a 1448380_at Res & Lgx Lgals3bp 1448388_a_at Lgx only 1110002B05Rik 1448402_at Lgx only Tln1 1448412_a_at Lgx only Tsc22d4 1448415_a_at Lgx only Sema3b 1448416_at Lgx only Mgp 1448417_at Lgx only Ninj1 1448429_at Res & Lgx Gyg 1448430_a_at CR & Lgx Naca 1448432_at Lgx only Plcd1 1448438_at Lgx only Derl2 1448463_at Lgx only 4933434E20Rik 1448467_a_at Lgx only Ehbp1l1 1448476_at CR & Lgx Nap1l4 1448480_at Res & Lgx Nip7 1448484_at Res & Lgx Amd1 1448488_at CR & Lgx Mrps5 1448492_a_at Res & Lgx Psmd12 1448493_at CR & Lgx Paip2 1448495_at Lgx only Tsta3 1448498_at Lgx only Rps6ka4 1448505_at Res & Lgx C1d 1448508_at Lgx only Traf3ip2 1448517_at Lgx only Timm22 1448527_at Lgx only Pdcd10 1448533_at Res & Lgx Tbcb 1448535_at Lgx only Elp4 1448536_at Lgx only Lsm3 1448537_at Res & Lgx Ttc1 1448543_at Res & Lgx Slmo2 1448548_at Lgx only Tulp4 1448549_a_at Res only Dpagt1 1448559_at Lgx only Flot1 1448564_at Res only Cib1 1448565_at Lgx only Ppp1r11 1448567_at Lgx only Tmem115 1448568_a_at CR only Slc20a1 1448570_at Lgx only Gmfb 1448579_at Lgx only Glg1 1448585_at Res only Gtf2h4 1448591_at CR only Ctss 1448613_at Lgx only Ecm1 1448615_at Res & Lgx Ccs 1448621_a_at Res & Lgx Smpd1 1448623_at Lgx only Tmem123 1448625_at Res & Lgx Golga2 1448637_at Lgx only Med25 1448638_at Res only Mtbp 1448644_at Lgx only Pef1 1448645_at Lgx only Msl31 1448649_at Lgx only Enpep 1448684_at Res & Lgx Ppp1r2 1448696_at Res only Heph 1448700_at Lgx only G0s2 1448717_at CR only Gcdh 1448720_at Lgx only Lrrc40 1448724_at Res only Cish 1448727_at Lgx only Tle6 1448729_a_at CR & Lgx 39329 1448737_at Lgx only Tspan7 1448760_at Lgx only Zfp68 1448762_at Res & Lgx Rad17 1448769_at Lgx only Slc35b1 1448770_a_at Lgx only Atpif1 1448771_a_at Lgx only Fth1 1448788_at Res & Lgx Cd200 1448792_a_at Res only Cyp2f2 1448797_at Res & Lgx Elk3 1448809_at Res & Lgx Cse1l 1448810_at Res & Lgx Gne 1448826_at Lgx only Myh6 1448830_at Lgx only Dusp1 1448835_at Res & Lgx E2f6 1448838_at Lgx only Topors 1448840_at Lgx only Tmub1 1448844_at Lgx only Cyb5b 1448853_at Lgx only Synj2bp 1448856_a_at Res & Lgx Msra 1448860_at Res only Rem2 1448864_at Lgx only Snrk 1448867_at Lgx only Tmem9b 1448883_at Lgx only Lgmn 1448884_at Lgx only Gtf2e2 1448885_at CR only Rap2b 1448893_at Lgx only Ncor2 1448894_at Lgx only Akr1b8 1448900_at Lgx only D16H22S680E 1448903_at Lgx only 39340 1448917_at Lgx only Med30 1448918_at Lgx only Slco3a1 1448943_at Lgx only Nrp1 1448947_at Lgx only 2810004N23Rik 1448948_at Lgx only Rag1ap1 1448956_at Lgx only Stard10 1448960_at Lgx only Cxxc5 1448970_at Lgx only Slc25a46 1448971_at Lgx only 2410022L05Rik 1448987_at Lgx only Acadl 1448993_at Res & Lgx Atg3 1449014_at Res only Lactb 1449025_at Lgx only Ifit3 1449026_at Res & Lgx Ifnar1 1449042_at Lgx only Ctcf 1449044_at Lgx only Eef1e1 1449045_at Lgx only Afg3l1 1449046_a_at Lgx only Josd2 1449058_at Lgx only Gli1 1449062_at Lgx only Khk 1449063_at Res only Sec22b 1449071_at Lgx only Myl7 1449072_a_at Lgx only N6amt2 1449078_at Res & Lgx St3gal6 1449080_at All Hdac2 1449088_at Lgx only Fbp2 1449096_at Lgx only Ccdc127 1449106_at Lgx only Gpx3 1449108_at Lgx only Fdx1 1449113_at Res only Gpbp1l1 1449123_at Lgx only Itih3 1449124_at Res & Lgx Rgl1 1449125_at Lgx only Tnfaip8l1 1449138_at Lgx only Sf3b1 1449140_at Lgx only Nudcd2 1449145_a_at Lgx only Cav1 1449151_at Lgx only Pctk3 1449187_at Lgx only Pdgfa 1449217_at Lgx only Casp8ap2 1449256_a_at Lgx only Rab11a 1449269_at Lgx only F5 1449281_at Lgx only Nrtn 1449298_a_at Lgx only Pde1a 1449300_at Lgx only Cttnbp2nl 1449304_at Lgx only 2310061J03Rik 1449333_at Lgx only Sf3a1 1449335_at Lgx only Timp3 1449338_at Lgx only D10Ertd641e 1449345_at Res only Ccdc34 1449348_at Lgx only Mpp6 1449354_at Res & Lgx Zrsr1 1449355_a_at Lgx only Eps15l1 1449356_at Lgx only Asb5 1449357_at Res & Lgx 2310030G06Rik 1449363_at Res only Atf3 1449368_at Lgx only Dcn 1449372_at Res only Dnajc3a 1449388_at Lgx only Thbs4 1449396_at Lgx only Aoc3 1449398_at Lgx only Rpl3l 1449400_at Lgx only Csl 1449408_at Lgx only Jam2 1449491_at Lgx only Card10 1449505_at Res & Lgx Kpna1 1449511_a_at Lgx only Ssbp4 1449514_at CR only Grk5 1449547_at Res & Lgx Asb14 1449551_at Lgx only Myo1c 1449553_at CR & Lgx 2610200G18Rik 1449566_at Lgx only Nkx2−5 1449575_a_at Res & Lgx Gstp1 1449588_at Lgx only Abca4 1449592_at CR only Tcf15 1449813_at Res only Zfp30 1449818_at CR only Abcb4 1449842_at Res & Lgx 1810059G22Rik 1449845_a_at Lgx only Ephb4 1449849_a_at Lgx only Fbxl6 1449851_at Lgx only Per1 1449852_a_at CR only Ehd4 1449860_at Lgx only Higd1b 1449872_at Lgx only Hspb3 1449935_a_at CR only Dnaja3 1449942_a_at Lgx only Ilk 1449944_a_at Res only Sec61a2 1449964_a_at Lgx only Mlycd 1449969_at Lgx only Tmod4 1450016_at Lgx only Ccng1 1450023_at Lgx only Gtpbp1 1450031_at Lgx only Aff4 1450054_at Lgx only Add1 1450067_a_at Res & Lgx 1810034K20Rik 1450086_at Lgx only Gmeb1 1450095_a_at Lgx only Acyp1 1450122_at Lgx only Ptprg 1450123_at Lgx only Ryr2 1450138_a_at Lgx only Serpinb6a 1450180_a_at Lgx only Rara 1450195_at Lgx only Ndst4 1450199_a_at Lgx only Stab1 1450203_at Lgx only Smyd1 1450308_a_at Res & Lgx Xrn1 1450355_a_at Res only Capg 1450361_at CR only Prop1 1450376_at Lgx only Mxi1 1450377_at Lgx only LOC640441 1450395_at Lgx only Slc22a5 1450405_at Res & Lgx Mrpl19 1450409_a_at Lgx only 4930570C03Rik 1450415_at CR only Pde6a 1450424_a_at CR only Il18bp 1450431_a_at Res & Lgx Nedd4 1450435_at Lgx only L1cam 1450449_a_at Lgx only 2900002H16Rik 1450490_at Lgx only Kcna7 1450519_a_at Lgx only Prkaca 1450531_at CR only H2−Bl 1450584_at Res only Hoxd11v 1450623_at Lgx only Gnb2v 1450627_at Res & Lgx Ank 1450649_at Lgx only Gng10 1450650_at Lgx only Myo10 1450662_at Lgx only Tesk1 1450664_at CR & Lgx Gabpa 1450670_at Lgx only Dbh 1450672_a_at Lgx only Trex1 1450678_at CR only Itgb2 1450690_at Lgx only Ranbp2 1450691_at Res only Caskin2 1450700_at Res & Lgx Cdc42ep3 1450706_a_at Lgx only Arl3 1450714_at Res & Lgx Azin1 1450729_at Lgx only Hs2st1 1450735_at Res & Lgx Pno1 1450738_at Lgx only Kif21a 1450740_a_at Res & Lgx Mapre1 1450744_at Lgx only Ell2 1450759_at Res only Bmp6 1450791_at Lgx only Nppb 1450798_at Lgx only Tnxb 1450801_at Res & Lgx Adam21 1450816_at Res only Polg2 1450839_at Res only D0H4S114 1450840_a_at Lgx only Rpl39 1450842_a_at CR & Lgx Cenpa 1450857_a_at Lgx only Col1a2 1450866_a_at Lgx only Mrpl17 1450878_at Lgx only Sri 1450879_at Lgx only Atp9b 1450883_a_at CR only Cd36 1450890_a_at Lgx only Abi1 1450891_at Lgx only Srp19 1450894_a_at Res & Lgx Ap2m1 1450897_at Lgx only Arhgap5 1450903_at Lgx only Rad23b 1450927_at Lgx only Lztr1 1450934_at Res & Lgx Eif4a2 1450948_a_at Lgx only Mrpl1 1450953_at Res & Lgx Ciao1 1450957_a_at Lgx only Sqstm1 1450958_at Lgx only Tm4sf1 1450965_at Res & Lgx Tex261 1450966_at Lgx only Crot 1450968_at Lgx only Uqcrfs1 1450970_at Lgx only Got1 1450971_at Res & Lgx Gadd45b 1450974_at Res & Lgx Timp4 1450994_at Lgx only Rock1 1451002_at Lgx only Aco2 1451006_at Lgx only Xdh 1451010_at Lgx only Nol11 1451017_at Lgx only Ergic3 1451019_at Lgx only Ctsf 1451022_at Lgx only Lrp6 1451025_at Lgx only Arl1 1451050_at Lgx only Nt5c3 1451051_a_at Lgx only Scyl1 1451067_at Lgx only Sgta 1451070_at Lgx only Gdi1 1451074_at Res & Lgx Rnf13 1451096_at Lgx only Ndufs2 1451099_at Lgx only Mbc2 1451104_a_at CR & Lgx Snrp70 1451118_a_at Lgx only 2410018C17Rik 1451119_a_at Lgx only Fbln1 1451121_a_at Res & Lgx Gltscr2 1451126_at Lgx only Maf1 1451134_a_at Res & Lgx Tm2d2 1451144_at All Bxdc2 1451159_at Res & Lgx Arhgef12 1451168_a_at Res & Lgx Arhgdia 1451177_at Res & Lgx Dnajb4 1451187_at Lgx only 0610037P05Rik 1451204_at Res only Scara5 1451217_a_at Lgx only Immp1l 1451219_at Lgx only Ormdl1 1451223_a_at Lgx only Btf3l4 1451225_at Lgx only Ptpn11 1451226_at Lgx only Pex6 1451232_at Lgx only Cd151 1451244_a_at Lgx only Zfp422 1451245_at Lgx only Lrrc3b 1451248_at Res & Lgx Prmt7 1451254_at Res & Lgx Ikbkap 1451269_at Lgx only Pdzd11 1451272_a_at Res & Lgx Ube2f 1451274_at Lgx only Ogdh 1451281_at Res only Zscan12 1451284_at Lgx only Yipf3 1451285_at Lgx only Fus 1451290_at Lgx only Map1lc3a 1451291_at CR only Obfc2b 1451293_at CR only Rrp9 1451295_a_at Res & Lgx Chd4 1451297_at Res only Gulo 1451298_at Lgx only Plekhh3 1451312_at Lgx only Ndufs7 1451316_a_at Res & Lgx Picalm 1451343_at Lgx only Vps36 1451344_at Lgx only Tmem119 1451349_at Lgx only BC020077 1451364_at Res & Lgx Polr3gl 1451369_at Lgx only Commd5 1451381_at Lgx only 1810020D17Rik 1451382_at Res & Lgx Chac1 1451388_a_at Lgx only Atp11b 1451405_at Lgx only Pcca 1451415_at CR only 1810011O10Rik 1451420_at Res & Lgx Ccdc47 1451427_a_at Lgx only Egfl7 1451448_a_at Lgx only 1110005A03Rik 1451453_at Lgx only Dapk2 1451455_at Res only Thnsl2 1451462_a_at Lgx only Ifnar2 1451465_at Lgx only Ubl7 1451471_at Lgx only Ears2 1451488_at Lgx only 1110028A07Rik 1451502_at CR only Pla2g10 1451508_at Lgx only Larp2 1451523_a_at Lgx only Mif4gd 1451538_at Lgx only Sox9 1451553_at Lgx only Art5 1451561_at Res & Lgx Prr12 1451583_a_at Res & Lgx BC025076 1451604_a_at Lgx only Acvrl1 1451622_at Lgx only Lmbrd1 1451663_a_at Lgx only Trim3 1451665_a_at Res & Lgx Ap4s1 1451674_at Lgx only Slc12a5 1451678_at Res & Lgx Narf 1451700_a_at Res & Lgx 1110007L15Rik 1451728_at Lgx only Wdr13 1451741_a_at Lgx only Cdk7 1451742_a_at Lgx only Ugp2 1451782_a_at Lgx only Slc29a1 1451789_a_at CR only Ryk 1451803_a_at Lgx only Vegfb 1451820_at Lgx only Diras1 1451839_a_at CR only Pde7a 1451854_a_at Lgx only Shroom3 1451857_a_at Lgx only Notum 1451883_at Res & Lgx ENSMUSG−00000074670 1451902_at Lgx only Zfp758 1451911_a_at Lgx only Ace 1451974_at Lgx only Osbpl2 1451984_at Res & Lgx Hnrpul1 1452012_a_at Lgx only Exosc1 1452024_a_at Lgx only Ldb1 1452043_at Lgx only 2310011J03Rik 1452047_at Res & Lgx Cacybp 1452057_at Lgx only Actr1b 1452058_a_at Res & Lgx Rnf11 1452072_at Res & Lgx Myct1 1452080_a_at Lgx only Dcun1d1 1452088_at Res only Zbed3 1452091_a_at CR & Lgx Rbm28 1452110_at Lgx only Mtrr 1452130_at Res & Lgx Txndc14 1452140_at Res & Lgx Tbc1d20 1452141_a_at Lgx only Sepp1 1452143_at All Spnb2 1452145_at Lgx only H6pd 1452152_at Lgx only Clint1 1452155_a_at Res & Lgx Ddx17 1452156_a_at Lgx only Nisch 1452159_at Res & Lgx 2310001A20Rik 1452173_at Lgx only Hadha 1452174_at Res & Lgx Srebf2 1452202_at Lgx only Pde2a 1452203_at All Obfc2a 1452208_at Lgx only Prdm4 1452213_at Res & Lgx Tex2 1452214_at Lgx only Skil 1452221_a_at Lgx only Cxxc1 1452222_at Lgx only Utrn 1452225_at Lgx only 2010106G01Rik 1452250_a_at Lgx only Col6a2 1452262_at Lgx only Grpel2 1452286_at Res & Lgx Slain2 1452291_at Lgx only Centd1 1452292_at Lgx only Ap2b1 1452296_at Lgx only Slit3 1452308_a_at Lgx only Atp1a2 1452309_at Lgx only Cgnl1 1452318_a_at Res & Lgx Hspa1b 1452319_at CR only Zfp82 1452327_at Lgx only Iqsec1 1452329_at Res & Lgx Plekhn1 1452330_a_at Lgx only Mxra8 1452333_at Res & Lgx Smarca2 1452335_at Res & Lgx Mfsd8 1452339_at Lgx only Adamts7 1452374_at Lgx only Zfp322a 1452375_at Lgx only Aldh4a1 1452395_at Res & Lgx Med19 1452398_at Lgx only Plce1 1452401_at Lgx only Wtap 1452411_at Lgx only Lrrc1 1452432_at Lgx only Tfpi 1452446_a_at Lgx only Tmub2 1452462_a_at Lgx only Banp 1452469_a_at Res & Lgx Smtn 1452472_at Lgx only Rtp3 1452499_a_at Res only Kif2a 1452502_at Lgx only ENSMUSG−00000050599 1452509_at CR only Usp9y 1452587_at Lgx only Actr2 1452596_at Lgx only Polr2k 1452601_a_at Lgx only Acbd6 1452607_at Lgx only 2610030H06Rik 1452608_at Res & Lgx Mycbp 1452625_at Lgx only Kctd2 1452653_at Lgx only Slc25a22 1452657_at Lgx only Ap1s2 1452661_at Res & Lgx Tfrc 1452689_at Res only Zfp512 1452694_at Lgx only Ihpk1 1452698_at Lgx only Tsfm 1452709_at Res & Lgx Poldip3 1452714_at Lgx only Tanc1 1452737_at Lgx only 2810008M24Rik 1452745_at Lgx only 1810044A24Rik 1452749_at Lgx only Papd1 1452753_at Res only Foxk2 1452761_a_at Lgx only 8430436O14Rik 1452767_at Lgx only Rrbp1 1452776_a_at Res only Nub1 1452813_a_at Res & Lgx Tmem188 1452843_at Res & Lgx Il6st 1452844_at Res only Pou6f1 1452856_at Res only Crebzf 1452866_at CR & Res Nars 1452867_at Lgx only Col4a3bp 1452871_at Lgx only Neil1 1452874_at Lgx only 2510003E04Rik 1452877_at Lgx only 2700029M09Rik 1452885_at Lgx only Sfrs2ip 1452897_at CR & Lgx Cdc2l5 1452901_at Lgx only Creb1 1452913_at Lgx only Pcp4l1 1452918_at Res & Lgx D19Ertd737e 1452920_a_at Lgx only Ppil2 1452952_at Res & Lgx 9030418K01Rik 1452953_at Res & Lgx Fam18b 1452960_at Lgx only Scyl3 1452965_at Res only Ankrd13d 1452972_at Lgx only Ttc32 1452977_at Lgx only Zhx3 1452985_at Lgx only Uaca 1452999_at Lgx only Smndc1 1453007_at CR only 3110082I17Rik 1453013_at Res & Lgx Zfp740 1453014_a_at Lgx only Sec31a 1453023_at Lgx only Ankhd1 1453028_at Lgx only 4631424J17Rik 1453039_at Lgx only Zfp335 1453058_at Lgx only Wdr5b 1453059_at Lgx only 2310046A06Rik 1453062_at CR only A930026I22Rik 1453097_a_at Lgx only Ubtf 1453119_at Res & Lgx Otud1 1453129_a_at Lgx only Rgs12 1453137_at Lgx only Fbxo30 1453149_at Lgx only Slc25a32 1453154_at CR only 1700029M20Rik 1453155_at Lgx only Tmem50a 1453160_at Lgx only Med13 1453180_at Res only 6530404N21Rik 1453187_at All Ociad2 1453191_at Lgx only Col27a1 1453196_a_at Res & Lgx Oasl2 1453206_at Res & Lgx Acad9 1453212_at Lgx only Zfp383 1453224_at Res & Lgx Zfand5 1453257_at Lgx only Agpat5 1453271_at Res & Lgx Phf14 1453296_at CR only Tmem103 1453312_at Lgx only Iqwd1 1453377_at Res & Lgx Sh2d4a 1453391_at CR only Speer7−ps1 1453399_at Res & Lgx Ccnt2 1453412_a_at CR only Sec14l1 1453486_a_at Lgx only Scube2 1453494_at Res only 4921513H07Rik 1453502_at Lgx only 2210408I21Rik 1453552_at CR & Lgx 2310014F07Rik 1453572_a_at Lgx only Plp2 1453592_at Lgx only Lrrc39 1453673_at Lgx only LOC100046982 1453728_a_at Lgx only Mrps17 1453729_a_at Lgx only Rpl37 1453731_a_at Lgx only Tmem77 1453739_at Res & Lgx Tmem126b 1453740_a_at Lgx only Ccnl2 1453761_at Res only Phf6 1453795_at Lgx only Fahd2a 1453804_a_at Lgx only Orc4l 1453821_at Res only N6amt1 1453850_at Lgx only 1500002I01Rik 1453851_a_at Lgx only Gadd45g 1453865_a_at Res & Lgx Otud5 1453866_a_at Lgx only Xk 1453898_at CR only Itgb1bp3 1453913_a_at Lgx only Tap2 1453976_at CR only 4432414F05Rik 1453983_a_at Lgx only Mett10d 1454017_at Res & Lgx 4921509O07Rik 1454020_at Lgx only 4930554H23Rik 1454021_a_at CR only Exosc10 1454023_a_at Lgx only D1Bwg1363e 1454034_a_at Lgx only Usp21 1454047_a_at CR only 2410017P07Rik 1454074_a_at Res & Lgx Rsrc2 1454092_a_at Res only Gtf2h3 1454109_a_at Res & Lgx Jmjd6 1454116_a_at Lgx only Mterfd1 1454189_at Lgx only 4930557J02Rik 1454206_a_at Lgx only Adam15 1454214_a_at Lgx only 2410019A14Rik 1454236_a_at Res only Ppp4r1l 1454395_at Lgx only 4632404M16Rik 1454455_at Lgx only 6530413G14Rik 1454466_at CR only 4933407I18Rik 1454606_at Lgx only 4933426M11Rik 1454611_a_at Res only Calm1 1454612_at Lgx only Mex3c 1454613_at Lgx only Dpysl3 1454619_at Lgx only Tmem112b 1454626_at Lgx only Cltc 1454631_at Lgx only Gtf2a1 1454638_a_at Lgx only Pah 1454644_at Lgx only 6330569M22Rik 1454645_at Res & Lgx Mgrn1 1454646_at Res only Tcp11l2 1454647_at Lgx only Acad11 1454654_at Lgx only Dirc2 1454658_at Res only Ilvbl 1454666_at Lgx only LOC100046855 1454670_at Lgx only Rere 1454679_at Lgx only D8Ertd457e 1454682_at Lgx only A430005L14Rik 1454693_at Lgx only Hdac4 1454697_at Lgx only Tloc1 1454704_at Lgx only Scarb2 1454706_at Res & Lgx Uvrag 1454709_at CR only Tmem64 1454718_at CR only Nagpa 1454723_at Lgx only 1110033M05Rik 1454727_at Lgx only Afap1l1 1454730_at All Tapt1 1454733_at Res only Nod1 1454739_at Res & Lgx Cdc27 1454745_at Lgx only Arhgap29 1454749_at Lgx only Pcnt 1454753_at Lgx only Rnpepl1 1454759_at Lgx only Git1 1454780_at Res & Lgx Galntl4 1454797_at Res & Lgx Tmem55b 1454801_at Lgx only Ankrd28 1454813_at Lgx only Ccdc72 1454820_at Res & Lgx BC037034 1454834_at Lgx only Nfib 1454848_at Lgx only Ppp1r12c 1454861_at Lgx only Txlna 1454868_at Lgx only D4Ertd429e 1454887_at Lgx only Pak2 1454888_at Res & Lgx Pfdn4 1454892_at Lgx only Pitpnb 1454894_at Lgx only LOC100045522 1454895_at Res & Lgx Cybasc3 1454906_at Res & Lgx Rarb 1454914_at Lgx only 2610101N10Rik 1454915_at Res & Lgx Rab3gap2 1454921_at Lgx only Gm561 1454922_at Res & Lgx Wdr92 1454928_at Lgx only Safb 1454930_at CR only Tbcel 1454934_at CR only Ppm1f 1454937_at Lgx only B630005N14Rik 1454938_at Lgx only Snx13 1454955_at Lgx only Ipo7 1454960_at Lgx only Smad3 1454964_at CR only BC021395 1454977_at Lgx only AU020772 1454979_at Lgx only Diap1 1454980_at Lgx only 4930402E16Rik 1454985_at Lgx only D030051N19Rik 1454991_at Res & Lgx Slc7a1 1454997_at CR only Msrb3 1455014_at Res & Lgx AV009015 1455018_at Lgx only Lmtk2 1455025_at Res only Paqr9 1455051_at Lgx only Rnf31 1455061_a_at Lgx only Acaa2 1455081_at Lgx only Txnl4b 1455082_at Lgx only Cblb 1455090_at Lgx only Angptl2 1455105_at Lgx only Ptpn12 1455118_at Res & Lgx D9Ertd402e 1455131_at Lgx only Opa3 1455142_at Lgx only Socs4 1455143_at Res & Lgx Nlgn2 1455152_at Res & Lgx AI462493 1455153_at Lgx only Zfp236 1455155_at Lgx only Lsm14b 1455157_a_at Res & Lgx BC039210 1455159_at Lgx only Appl1 1455164_at Lgx only Cdgap 1455166_at Res & Lgx Arl5b 1455188_at Res only Ephb1 1455197_at Res only Rnd1 1455204_at Res & Lgx Pitpnc1 1455205_a_at Lgx only Usp19 1455207_at Lgx only 2410017P09Rik 1455210_at Lgx only Zhx2 1455226_at Res & Lgx Spnb1 1455244_at Res & Lgx Daam1 1455267_at Lgx only Esrrg 1455268_at Res & Lgx Dph3 1455285_at Res & Lgx Slc31a1 1455288_at Res & Lgx 1110036O03Rik 1455293_at Lgx only Leo1 1455296_at Lgx only LOC100047385 1455300_at Res & Lgx E130014J05Rik 1455307_at Lgx only BC037112 1455309_at Res & Lgx Tmem16f 1455312_at Lgx only Phc3 1455320_at CR & Lgx AI480535 1455340_at Res & Lgx D030011O10Rik 1455349_at Lgx only LOC100048397 1455353_at Lgx only Tmcc1 1455356_at Lgx only Camsap1 1455387_at Res & Lgx Nufip2 1455390_at Lgx only Alkbh6 1455434_a_at Res & Lgx Ktn1 1455442_at Res & Lgx Slc6a19 1455450_at Lgx only Ptpn3 1455456_a_at Lgx only Timm50 1455462_at Res & Lgx Adcy2 1455479_a_at Res & Lgx Ube2d3 1455482_at All Ap2a2 1455491_at Res & Lgx Hnrph3 1455506_at Lgx only Slc25a34 1455508_at Lgx only A530082C11Rik 1455538_at Lgx only 6330403M23Rik 1455585_at Lgx only Rnf168 1455587_at Res only BC030183 1455588_at Res & Lgx Lyrm4 1455655_a_at Res & Lgx Tardbp 1455688_at Lgx only Ddr2 1455689_at Lgx only Fzd10 1455700_at Res & Lgx Mterfd3 1455702_at Lgx only Wdr22 1455733_at Res & Lgx Taok3 1455734_at CR & Lgx Crbn 1455741_a_at Res & Lgx Ece1 1455750_at Res & Lgx A230067G21Rik 1455757_at Res & Lgx D3Ertd254e 1455794_at Lgx only Smtnl2 1455832_a_at Res only Umps 1455854_a_at Res & Lgx Ssh1 1455870_at Lgx only Akap2 1455873_a_at Lgx only Vps18 1455884_at Lgx only Dpp9 1455914_at Lgx only AI987944 1455915_at CR only Galnt4 1455922_at Lgx only Rab3gap1 1455936_a_at CR & Lgx Rbpms 1455944_at Lgx only Zfp516 1455945_at Lgx only Zfp817 1456046_at Lgx only Cd93 1456058_at Lgx only Rbm27 1456059_at Lgx only Psmd11 1456061_at Res & Lgx Gimap8 1456065_at CR only Ubash3a 1456092_at Lgx only Kctd7 1456099_at Res only D930017J03Rik 1456161_at Lgx only 0610040B10Rik 1456169_at Res only EG226654 1456210_at Lgx only 5430407P10Rik 1456241_a_at Lgx only 1810073N04Rik 1456257_at Res only C130065N10Rik 1456315_a_at Res & Lgx Ptpla 1456398_at Lgx only Tug1 1456487_at Lgx only Adcy1 1456599_at CR only Nxt2 1456604_a_at Lgx only Pcmt1 1456611_at Lgx only D430015B01Rik 1456625_at Lgx only Aasdhppt 1456643_at Lgx only 9230114K14Rik 1456659_at Lgx only LOC552902 1456727_a_at Res & Lgx Csnk1d 1456768_a_at Lgx only Mmrn2 1456774_at Lgx only Ppp1r13l 1456777_at CR & Lgx Mgam 1456827_at Lgx only AA987161 1456836_at CR only Itk 1456871_a_at Res only Phf20l1 1456888_at Lgx only Pfkfb4 1456896_at Res only 6720462K09Rik 1456914_at Lgx only Slc16a4 1457058_at Lgx only Adamts2 1457111_at Res only AA415038 1457276_at Res only Snf1lk2 1457285_at Lgx only Zfp187 1457334_at All C130057M05Rik 1457401_at Lgx only Dnahc9 1457448_at CR only Pnpla1 1457501_at Res only RP23−233B9.8 1457508_at Res & Lgx C430003N24Rik 1457557_at Lgx only A330076H08Rik 1457626_at Res only D3Wsu106e 1457671_at Lgx only 9330120H11Rik 1457681_at Lgx only 2610301F02Rik 1457707_at Res & Lgx Mctp2 1457745_at Res only Gpr4 1457747_at Res only 9330109K16Rik 1457801_at CR only 9930024M15Rik 1458058_at Lgx only 7030407E18Rik 1458190_at Res only Arhgap4 1458311_at Res only Usp36 1458353_at Res only Nwd1 1458438_at Lgx only Ccdc122 1458455_at Lgx only Abra 1458461_at Res only E330021D16Rik 1458478_at Res only 9230110F11Rik 1458482_at Lgx only Tnni3k 1458624_at Res & Lgx Rbm24 1458780_at Res only D8Ertd620e 1458863_at Res only 6330415G19Rik 1459108_a_at Res & Lgx Yeats2 1459220_at Lgx only C78651 1459363_at Lgx only Atxn2 1459578_at Res only AA407175 1460033_at CR only C030002C11Rik 1460053_at CR only Smyd4 1460113_at CR only B930093H17Rik 1460165_at Res & Lgx Ppp1ca 1460167_at Lgx only Aldh7a1 1460169_a_at Lgx only Pctk1 1460177_at Res & Lgx Cndp2 1460184_at Lgx only Hadh 1460189_at Res & Lgx Wdr23 1460194_at Lgx only Phyh 1460196_at Lgx only Cbr1 1460210_at Lgx only Pkd1 1460214_at CR only Pcp4 1460216_at Lgx only Acads 1460230_at Lgx only Syn2 1460239_at Lgx only Tspan13 1460251_at Lgx only Fas 1460254_at Res & Lgx 1810049H13Rik 1460271_at CR only Trem3 1460276_a_at Lgx only Gpr175 1460321_at CR only Cntn4 1460326_at Res & Lgx Pik3ca 1460328_at Res & Lgx Brd3 1460329_at Res only LOC675709 1460330_at Lgx only Anxa3 1460331_at Res & Lgx Tm9sf2 1460336_at Lgx only Ppargc1a 1460337_at CR only Sh3kbp1 1460344_at Lgx only 2310033F14Rik 1460396_at Lgx only Ddx54 1460409_at Lgx only Cpt1a 1460412_at CR only 1600015H20Rik 1460420_a_at Lgx only Egfr 1460428_at Lgx only Ankrd13a 1460432_a_at Lgx only Eif3e 1460433_at Lgx only Entpd6 1460435_at Lgx only 1500002O20Rik 1460444_at Lgx only Arrb1 1460500_at Lgx only 5033421C21Rik 1460510_a_at Res & Lgx Coq10b 1460539_at Res only 4933404K13Rik 1460547_a_at Res & Lgx Hnrpk 1460552_at Lgx only Ascc3l1 1460557_at Lgx only Supv3l1 1460559_at Lgx only Ankrd25 1460570_at Lgx only Pgbd5 1460573_at Res & Lgx AI848100 1460576_at Res & Lgx LOC100047539 1460580_at Lgx only Pcnx 1460586_at Lgx only Megf8 1460603_at Res only Samd9l 1460607_at CR only Igsf11 1460610_at Lgx only Agbl5 1460614_at Lgx only LOC100045020 1460624_at Res & Lgx 6330564D18Rik 1460643_at Lgx only Ell 1460644_at Lgx only Bckdk 1460645_at Res & Lgx Chordc1 1460648_at Lgx only Nr2f6 1460674_at Lgx only Paqr7 1460675_at Lgx only Igsf8 1460695_a_at Lgx only 2010111I01Rik 1460704_at Lgx only Rfng 1460716_a_at Lgx only Cbfb 1460720_at Res & Lgx Trpc4ap 1460732_a_at Lgx only Ppl AFFX−b−ActinMur Res & Lgx Actb M12481_3_at Res & Lgx Actb AFFX−GapdhMur Lgx only Gapdh M32599_M_at Lgx only Gapdh 

1-20. (canceled)
 21. A method for administering a cardioprotective agent to a human subject, the method comprising: administering to a human subject in need thereof, a therapeutically effective amount of a composition comprising: trans-resveratrol; a metal chelating agent; and one or more additional antioxidants, wherein the therapeutically effective amount of the composition is sufficient to provide an improved cardioprotective effect in the human subject as compared to administration of resveratrol alone.
 22. The method of claim 21, wherein trans-resveratrol is present in an amount of 0.25 to 30 mg per kilogram of the human subject.
 23. The method of claim 22, wherein trans-resveratrol is present in an amount of 0.25 to 5 mg per kilogram of the human subject.
 24. The method of claim 21, wherein the metal chelating agent is present in an amount of 0.25 to 5 mg per kilogram of the human subject.
 25. The method of claim 24, wherein the metal chelating agent comprises phytic acid.
 26. The method of claim 21, wherein the one or more additional antioxidants are present in an amount of 0.05 to 2 mg per kilogram of the human subject.
 27. The method of claim 26, wherein the one or more additional antioxidants comprises a phenolic antioxidant.
 28. The method of claim 27 wherein the phenolic antioxidant is selected from the group consisting of apigenin, caffeic acid, epigallocatechin 3-gallate (EGCG), ferulic acid, and quercetin.
 29. The method of claim 26, wherein the one or more additional antioxidants comprises Vitamin D.
 30. The method of claim 21, wherein the composition further comprises one or more glycosaminoglycans selected from the group consisting of hyaluronic acid and chondroitin sulfate.
 31. The method of claim 21, wherein the therapeutically effective amount of the composition is sufficient to provide the cardioprotective effect of reducing myocardial infarct size as compared to administration of resveratrol alone.
 32. The method of claim 21, wherein the therapeutically effective amount of the composition is sufficient to provide the cardioprotective effect of an improved cardiac output function as compared to administration of resveratrol alone.
 33. The method of claim 32, wherein the cardiac output function is assessed by measuring one or more of the following: aortic flow, coronary flow, left ventricular developed pressure, and first derivative of left ventricular developed pressure.
 34. The method of claim 21, wherein the therapeutically effective amount of the composition is sufficient to provide the cardioprotective effect of reducing cardiomyocyte apoptosis to a greater degree than administration of resveratrol alone.
 35. The method of claim 21, wherein the composition provides a cardioprotective effect by preconditioning, causing the upregulation of one or molecules involved in intracellular stress signaling pathways.
 36. The method of claim 21, wherein the composition is administered prophylactically.
 37. A method for administering a cardioprotective agent to a human subject, the method comprising: administering to a human subject in need thereof, a therapeutically effective amount of a composition comprising: trans-resveratrol present in an amount of 0.25 to 5 mg per kilogram of the human subject; phytic acid present in an amount of 0.25 to 5 mg per kilogram of the human subject; and one or more additional antioxidants present in an amount of 0.05 to 2 mg per kilogram of the human subject, wherein the therapeutically effective amount of the composition is sufficient to provide an improved cardioprotective effect in the human subject as compared to administration of resveratrol alone.
 38. The method of claim 37, wherein the phenolic antioxidant is quercetin.
 39. The method of claim 37, wherein the composition is administered prophylactically.
 40. The method of claim 39, wherein the composition provides a cardioprotective effect against an ischemic event. 